Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Alport syndrome—insights from basic and clinical research

Nature Reviews Nephrology volume 9, pages 170–178 (2013)Cite this article

Subjects

Abstract

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.

Key Points

  • Alport syndrome, a hereditary disorder associated with mutations in type IV collagen, is characterized by hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure

  • Diagnosis requires careful evaluations of the patient's family history as well as their renal, ocular and auditory function; genotyping and electron microscopy of kidney biopsy samples can also be useful

  • First-line treatment with angiotensin-converting-enzyme inhibitors should be initiated at the latest in patients with stage 2 Alport syndrome (proteinuria >300 mg per day)

  • Treatment of children at earlier stages of Alport syndrome (stages 0 or 1, corresponding to haematuria or microalbuminuria) should only take place in the setting of controlled trials such as EARLY PRO-TECT Alport

  • Therapeutic decision-making should take into account the patient's sex, stage of disease, mutation type, and family history (especially age at onset of end-stage renal disease in affected relatives)

  • Potential new podocyte-targeted therapeutic approaches for Alport syndrome include anti-inflammatory or bone morphogenic protein-7-like molecules, protease inhibitors, collagen-receptor blockers and cell-based therapies that target podocytes

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential mechanisms underlying chronic renal disease occurring in Alport syndrome.
Figure 2: Kidney pathology in Alport syndrome.

Similar content being viewed by others

References

  1. Alport, A. C. Hereditary familial congenital haemorrhagic nephritis. Br. Med. J. 1, 504–506 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Williamson, D. A. Alport's syndrome of hereditary nephritis with deafness. Lancet 2, 1321–1323 (1961).

    Article  CAS  PubMed  Google Scholar 

  3. Nagel, M., Nagorka, S. & Gross, O. Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum. Mutat. 26, 60 (2005).

    Article  PubMed  Google Scholar 

  4. Hertz, J. M., Thomassen, M., Storey, H. & Flinter, F. Clinical utility gene card for: Alport syndrome. Eur. J. Hum. http://dx.doi.org/10.1038/ejhg.2011.237.

  5. Antignac, C. Molecular genetics of basement membranes: the paradigm of Alport syndrome. Kidney Int. Suppl. 49, S29–S33 (1995).

    CAS  PubMed  Google Scholar 

  6. Flinter, F. A., Cameron, J. S., Chantler, C., Houston, I. & Bobrow, M. Genetics of classic Alport's syndrome. Lancet 2, 1005–1007 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Jais, J. P. et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study. J. Am. Soc. Nephrol. 14, 2603–2610 (2003).

    Article  PubMed  Google Scholar 

  8. Gross, O., Netzer, K. O., Lambrecht, R., Seibold, S. & Weber, M. Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol. Dial. Transplant. 17, 1218–1227 (2002).

    Article  PubMed  Google Scholar 

  9. Bekheirnia, M. R. et al. Genotype–phenotype correlation in X-linked Alport syndrome. J. Am. Soc. Nephrol. 21, 876–883 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gross, O. & Weber, M. From the molecular genetics of Alport's syndrome to principles of organo-protection in chronic renal diseases [German]. Med. Klin. (Munich) 100, 826–831 (2005).

    Article  CAS  Google Scholar 

  11. Temme, J. et al. Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int. 81, 779–783 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Migeon, B. R. X inactivation, female mosaicism, and sex differences in renal diseases. J. Am. Soc. Nephrol. 19, 2052–2059 (2008).

    Article  PubMed  Google Scholar 

  13. Gross, O. et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 81, 494–501 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Khoshnoodi, J., Pedchenko, V. & Hudson, B. G. Mammalian collagen IV. Microsc. Res. Tech. 71, 357–370 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hudson, B. G. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J. Am. Soc. Nephrol. 15, 2514–2527 (2004).

    Article  PubMed  Google Scholar 

  16. Poschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Ninomiya, Y. et al. Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies. J. Cell Biol. 130, 1219–1229 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Kalluri, R., Shield, C. F., Todd, P., Hudson, B. G. & Neilson, E. G. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J. Clin. Invest. 99, 2470–2478 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cosgrove, D., Kornak, J. M. & Samuelson, G. Expression of basement membrane type IV collagen chains during postnatal development in the murine cochlea. Hear. Res. 100, 21–32 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Zehnder, A. F. et al. Distribution of type IV collagen in the cochlea in Alport syndrome. Arch. Otolaryngol. Head Neck Surg. 131, 1007–1013 (2005).

    Article  PubMed  Google Scholar 

  21. Kerjaschki, D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J. Clin. Invest. 108, 1583–1587 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hudson, B. G., Tryggvason, K., Sundaramoorthy, M. & Neilson, E. G. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N. Engl. J. Med. 348, 2543–2556 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. van Agtmael, T. & Bruckner-Tuderman, L. Basement membranes and human disease. Cell Tissue Res. 339, 167–188 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Wiradjaja, F., DiTommaso, T. & Smyth, I. Basement membranes in development and disease. Birth Defects Res. C Embryo Today 90, 8–31 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Kruegel, J. & Miosge, N. Basement membrane components are key players in specialized extracellular matrices. Cell. Mol. Life Sci. 67, 2879–2895 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cosgrove, D. Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr. Nephrol. 27, 885–890 (2012).

    Article  PubMed  Google Scholar 

  27. Mathew, S., Chen, X., Pozzi, A. & Zent, R. Integrins in renal development. Pediatr. Nephrol. 27, 891–900 (2012).

    Article  PubMed  Google Scholar 

  28. Welsh, G. I. & Saleem, M. A. The podocyte cytoskeleton—key to a functioning glomerulus in health and disease. Nat. Rev. Nephrol. 8, 14–21 (2012).

    Article  CAS  Google Scholar 

  29. Abrahamson, D. R., Hudson, B. G., Stroganova, L., Borza, D. B. & St. John, P. L. Cellular origins of type IV collagen networks in developing glomeruli. J. Am. Soc. Nephrol. 20, 1471–1479 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. LeBleu, V. et al. Identification of the NC1 domain of α3 chain as critical for α3α4α5 type IV collagen network assembly. J. Biol. Chem. 285, 41874–41885 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harvey, S. J. et al. Role of distinct type IV collagen networks in glomerular development and function. Kidney Int. 54, 1857–1866 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Abrahamson, D. R., Prettyman, A. C., Robert, B. & St. John, P. L. Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int. 63, 826–834 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Miner, J. H. Organogenesis of the kidney glomerulus: focus on the glomerular basement membrane. Organogenesis 7, 75–82 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kashtan, C. E. et al. Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: aberrant laminin α2 deposition is species independent. J. Am. Soc. Nephrol. 12, 252–260 (2001).

    CAS  PubMed  Google Scholar 

  35. Hamano, Y. et al. Determinants of vascular permeability in the kidney glomerulus. J. Biol. Chem. 277, 31154–31162 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Matsusaka, T. et al. Podocyte injury damages other podocytes. J. Am. Soc. Nephrol. 22, 1275–1285 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kriz, W. The pathogenesis of 'classic' focal segmental glomerulosclerosis-lessons from rat models. Nephrol. Dial. Transplant. 18 (Suppl. 6), vi39–vi44 (2003).

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Zeisberg, M. & Neilson, E. G. Mechanisms of tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 21, 1819–1834 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Smith, R. J., Steel, K. P., Barkway, C., Soucek, S. & Michaels, L. A histologic study of nonmorphogenetic forms of hereditary hearing impairment. Arch. Otolaryngol. Head Neck Surg. 118, 1085–1094 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Cosgrove, D. et al. Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome. Hear. Res. 121, 84–98 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Gratton, M. A., Rao, V. H., Meehan, D. T., Askew, C. & Cosgrove, D. Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome: implications for capillary basement membrane pathology. Am. J. Pathol. 166, 1465–1474 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Meehan, D. T. et al. Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney Int. 76, 968–976 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Cosgrove, D. et al. Integrin α1β1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome. Am. J. Pathol. 172, 761–773 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vogel, W. et al. Discoidin domain receptor 1 is activated independently of β1 integrin. J. Biol. Chem. 275, 5779–5784 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Meyer zum Gottesberge, A. M., Gross, O., Becker-Lendzian, U., Massing, T. & Vogel, W. F. Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1. Lab. Invest. 88, 27–37 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Gross, O. et al. DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria. Kidney Int. 66, 102–111 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Girgert, R. et al. Integrin α2-deficient mice provide insights into specific functions of collagen receptors in the kidney. Fibrogenesis Tissue Repair 3, 19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Roselli, S. et al. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol. Cell. Biol. 24, 550–560 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Done, S. C. et al. Nephrin is involved in podocyte maturation but not survival during glomerular development. Kidney Int. 73, 697–704 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Kashtan, C. E. et al. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-012-2138-4.

  52. Hertz, J. M. Alport syndrome. Molecular genetic aspects. Dan. Med. Bull. 56, 105–152 (2009).

    PubMed  Google Scholar 

  53. Artuso, R. et al. Advances in Alport syndrome diagnosis using next-generation sequencing. Eur. J. Hum. Genet. 20, 5057 (2012).

    Article  CAS  Google Scholar 

  54. Heidet, L. & Gubler, M. C. The renal lesions of Alport syndrome. J. Am. Soc. Nephrol. 20, 1210–1215 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Copelovitch, L. & Kaplan, B. S. Is genetic testing of healthy pre-symptomatic children with possible Alport syndrome ethical? Pediatr. Nephrol. 21, 455–456 (2006).

    Article  PubMed  Google Scholar 

  56. Zhang, K. W. et al. The use of ocular abnormalities to diagnose X-linked Alport syndrome in children. Pediatr. Nephrol. 23, 1245–1250 (2008).

    Article  PubMed  Google Scholar 

  57. Tan, R., Colville, D., Wang, Y. Y., Rigby, L. & Savige, J. Alport retinopathy results from “severe” COL4A5 mutations and predicts early renal failure. Clin. J. Am. Soc. Nephrol. 5, 34–38 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Fawzi, A. A., Lee, N. G., Eliott, D., Song, J. & Stewart, J. M. Retinal findings in patients with Alport Syndrome: expanding the clinical spectrum. Br. J. Ophthalmol. 93, 1606–1611 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Savige, J. et al. Retinal basement membrane abnormalities and the retinopathy of Alport syndrome. Invest. Ophthalmol. Vis. Sci. 51, 1621–1627 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Walia, S., Fishman, G. A. & Kapur, R. Flecked-retina syndromes. Ophthalmic Genet. 30, 69–75 (2009).

    Article  PubMed  Google Scholar 

  61. Citirik, M., Batman, C., Men, G., Tuncel, M. & Zilelioglu, O. Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome. Clin. Exp. Optom. 90, 367–370 (2007).

    Article  PubMed  Google Scholar 

  62. Choi, J., Na, K., Bae, S. & Roh, G. Anterior lens capsule abnormalities in Alport syndrome. Korean J. Ophthalmol. 19, 84–89 (2005).

    Article  PubMed  Google Scholar 

  63. Colville, D. J. & Savige, J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. 18, 161–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Wilson, M. E. Jr, Trivedi, R. H., Biber, J. M. & Golub, R. Anterior capsule rupture and subsequent cataract formation in Alport syndrome. J. AAPOS 10, 182–183 (2006).

    Article  PubMed  Google Scholar 

  65. Colville, D. et al. Ocular manifestations of autosomal recessive Alport syndrome. Ophthalmic Genet. 18, 119–128 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Ohkubo, S. et al. Immunohistochemical and molecular genetic evidence for type IV collagen α5 chain abnormality in the anterior lenticonus associated with Alport syndrome. Arch. Ophthalmol. 121, 846–850 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Harvey, S. J. et al. The inner ear of dogs with X-linked nephritis provides clues to the pathogenesis of hearing loss in X-linked Alport syndrome. Am. J. Pathol. 159, 1097–1104 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhang, X., Zhou, J., Reeders, S. T. & Tryggvason, K. Structure of the human type IV collagen COL4A6 gene, which is mutated in Alport syndrome-associated leiomyomatosis. Genomics 33, 473–479 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Miner, J. H. Alport syndrome with diffuse leiomyomatosis. When and when not? Am. J. Pathol. 154, 1633–1635 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Uliana, V. et al. Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2. Pediatr. Nephrol. 26, 717–724 (2011).

    Article  PubMed  Google Scholar 

  71. Vaicys, C., Hunt, C. D. & Heary, R. F. Ruptured intracranial aneurysm in an adolescent with Alport's syndrome—a new expression of type IV collagenopathy: case report. Surg. Neurol. 54, 68–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Kashtan, C. E. et al. Aortic abnormalities in males with Alport syndrome. Nephrol. Dial. Transplant. 25, 3554–3560 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Canpolat, U., Aytemir, K. & Tokgozoglu, L. Two-in-one: single coronary ostium and mitral valve prolapsus in a young female with Alport syndrome. Anadolu Kardiyol. Derg. 12, 281 (2012).

    PubMed  Google Scholar 

  74. Bassareo, P. P., Marras, A. R. & Mercuro, G. Ventricular septal defect in a child with Alport syndrome: a case report. BMC Cardiovasc. Disord. 10, 48 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Karamatic Crew, V. et al. CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood 104, 2217–2223 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Sachs, N. et al. Kidney failure in mice lacking the tetraspanin CD151. J. Cell Biol. 175, 33–39 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sachs, N. et al. Blood pressure influences end-stage renal disease of Cd151 knockout mice. J. Clin. Invest. 122, 348–358 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Yang, X. H. et al. CD151 restricts the α6 integrin diffusion mode. J. Cell Sci. 125, 1478–1487 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Heeringa, S. F. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J. Clin. Invest. 121, 2013–2024 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ishida, M., Mori, Y., Ota, N., Inaba, T. & Kunishima, S. Association of a novel in-frame deletion mutation of the MYH9 gene with end-stage renal failure: case report and review of the literature. Clin. Nephrol. http://dx.doi.org/10.5414/CN107237.

  81. Muller, T. et al. Non-muscle myosin IIA is required for the development of the zebrafish glomerulus. Kidney Int. 80, 1055–1063 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Izzi, C. et al. The Case | familial occurrence of retinitis pigmentosa, deafness, and nephropathy. Kidney Int. 79, 691–692 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Girard, D. & Petrovsky, N. Alström syndrome: insights into the pathogenesis of metabolic disorders. Nat. Rev. Endocrinol. 7, 77–88 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Bockenhauer, D. et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N. Engl. J. Med. 360, 1960–1970 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Reichold, M. et al. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc. Natl Acad. Sci. USA 107, 14490–14495 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Karet, F. E. et al. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat. Genet. 21, 84–90 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Sethi, S. K., Singh, N., Gil, H. & Bagga, A. Genetic studies in a family with distal renal tubular acidosis and sensorineural deafness. Indian Pediatr. 46, 425–427 (2009).

    PubMed  Google Scholar 

  88. Wuhl, E., Mehls, O. & Schaefer, F. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int. 66, 768–776 (2004).

    Article  PubMed  Google Scholar 

  89. Wuhl, E. et al. Strict blood-pressure control and progression of renal failure in children. N. Engl. J. Med. 361, 1639–1650 (2009).

    Article  PubMed  Google Scholar 

  90. Ellis, D., Moritz, M. L., Vats, A. & Janosky, J. E. Antihypertensive and renoprotective efficacy and safety of losartan. A long-term study in children with renal disorders. Am. J. Hypertens. 17, 928–935 (2004).

    CAS  PubMed  Google Scholar 

  91. Webb, N. J. et al. Efficacy and safety of losartan in children with Alport syndrome—results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial. Nephrol. Dial. Transplant. 26, 2521–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Gross, O. et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 63, 438–446 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Grodecki, K. M. et al. Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme (ACE) inhibitor. J. Comp. Pathol. 117, 209–225 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Gross, O. et al. Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis. Nephrol. Dial. Transplant. 19, 1716–1723 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Kagami, S. Involvement of glomerular renin-angiotensin system (RAS) activation in the development and progression of glomerular injury. Clin. Exp. Nephrol. 16, 214–220 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Matsuo, K., Tudor, E. L. & Baschat, A. A. Alport syndrome and pregnancy. Obstet. Gynecol. 109, 531–532 (2007).

    Article  PubMed  Google Scholar 

  97. Crovetto, F. et al. Pregnancy in women with Alport syndrome. Int. Urol. Nephrol. http://dx.doi.org/10.1007/s11255-012-0154-8.

  98. Gross, O. et al. Safety and efficacy of the ACE-inhibitor ramipril in Alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr. http://dx.doi.org/10.5402/2012/436046.

  99. Sayers, R. et al. Role for transforming growth factor-β1 in alport renal disease progression. Kidney Int. 56, 1662–1673 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Zeisberg, M. et al. Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med. 3, e100 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Koepke, M. L. et al. Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome. Nephrol. Dial. Transplant. 22, 1062–1069 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Ninichuk, V. et al. Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease. J. Am. Soc. Nephrol. 16, 977–985 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Zeisberg, M. et al. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am. J. Physiol. Renal. Physiol. 285, F1060–F1067 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Ninichuk, V. et al. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int. 70, 121–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Gross, O. et al. Stem cell therapy for Alport syndrome: the hope beyond the hype. Nephrol. Dial. Transplant. 24, 731–734 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. LeBleu, V. et al. Stem cell therapies benefit Alport syndrome. J. Am. Soc. Nephrol. 20, 2359–2370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sedrakyan, S. et al. Injection of amniotic fluid stem cells delays progression of renal fibrosis. J. Am. Soc. Nephrol. 23, 661–673 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Katayama, K. et al. Irradiation prolongs survival of Alport mice. J. Am. Soc. Nephrol. 19, 1692–1700 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Baum, A. et al. Searching biomarker candidates in serum using multidimensional native chromatography. II Method evaluation with Alport syndrome and severe inflammation. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 876, 31–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Obara, T., Mizoguchi, S., Shimozuru, Y., Sato, T. & Hotta, O. The complex of immunoglobulin A and uromodulin as a diagnostic marker for immunoglobulin A nephropathy. Clin. Exp. Nephrol. 16, 713–721 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zheng, M. et al. Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy. PLoS ONE 6, e20431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gross, O. et al. Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease. Matrix Biol. 29, 346–356 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Kasthan, C. E. & Segal, Y. Genetic disorders of the glomerular basement membranes. Nephron Clin. Pract. 118, c9–c18 (2011).

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the members of their group for helpful discussions, and would also like to thank the editorial team from Nature Reviews Nephrology for their editorial assistance. O. Gross is or has been supported by grants from the German Kidney Foundation, the Cologne Fortune Program of the University Cologne, the German Research Foundation (DFG GR 1852/4-1 and 4-2), the Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG-France), the KfH Foundation Preventive Medicine (Fritz-Scheler Stipendium of the German Society of Nephrology), and the German Federal Ministry of Education and Research (BMBF Program, Clinical Trials, 01KG1104).

Author information

Authors and Affiliations

  1. Department of Nephrology and Rheumatology, University Medicine Göttingen, Robert-Koch-Straße 40, Göttingen, 37075, Germany

    Jenny Kruegel, Diana Rubel & Oliver Gross

Authors
  1. Jenny Kruegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diana Rubel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Oliver Gross.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kruegel, J., Rubel, D. & Gross, O. Alport syndrome—insights from basic and clinical research. Nat Rev Nephrol 9, 170–178 (2013). https://doi.org/10.1038/nrneph.2012.259

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.259

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing