Skip to main content

Advertisement

Log in

Familial hematurias: what we know and what we don’t

  • Editorial Commentary
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Over the past 30 years we have learned a great deal about the molecular genetics and natural history of familial forms of hematuria. Our enhanced understanding of these conditions has yet to generate effective therapies for Alport syndrome, the form of familial hematuria associated with end-stage renal disease. This review briefly presents the current state of knowledge about familial hematuria and argues for the organization of clinical therapeutic trials in Alport syndrome.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

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

    Google Scholar 

  2. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227

    Google Scholar 

  3. Lemmink HH, Schröder CH, Monnens LAH, Smeets HJM (1997) The clinical spectrum of type IV collagen mutations. Hum Mutat 9:477–499

    Google Scholar 

  4. Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, Verellen-Dumoulin C, Chan B, Schroeder CH, Smeets HJM, Reeders ST (1994) Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genetics 8:77–82

    Google Scholar 

  5. Ding J, Stitzel J, Berry P, Hawkins E, Kashtan C (1995) Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. J Amer Soc Nephrol 5:1714–1717

    Google Scholar 

  6. Knebelmann B, Forestier L, Drouot L, Quinones S, Chuet C, Benessy F, Saus J, Antignac C (1995) Splice-mediated insertion of an Alu sequence in the COL4A3 mRNA causing autosomal recessive Alport syndrome. Hum Mol Genet 4:675–679

    Google Scholar 

  7. Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L, Cochat P, Grunfeld J-P, Palcoux J-B, Gubler M-C, Antignac C (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63:1329–1340

    Google Scholar 

  8. Longo I, Porcedda P, Mari F, Grachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, A. M, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61:1947–1956

    Google Scholar 

  9. Lemmink HH, Nillesen WN, Mochizuki T, Schröder CH, Brunner HG, van Oost BA, Monnens LAH, Smeets HJM (1996) Benign familial hematuria due to mutation of the type IV collagen α4 gene. J Clin Invest 98:1114–1118

    Google Scholar 

  10. Buzza M, Wang YY, Dagher H, Babon JJ, Cotton RG, Powell H, Dowling J, Savige J (2001) COL4A4 mutation in thin basement membrane disease previously described in Alport syndrome. Kidney Int 60:480–483

    Google Scholar 

  11. Buzza M, Dagher H, Wang YY, Wilson D, Babon JJ, Cotton RG, Savige J (2003) Mutations in the COL4A4 gene in thin basement membrane disease. Kidney Int 63:447–453

    Google Scholar 

  12. van der Loop FTL, Heidet L, Timmer EDJ, van den Bosch BJC, Leinonen A, Antiganc C, Jefferson JA, Maxwell AP, Monnens LAH, Schroder CH, Smeets HJM (2000) Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int 58:1870–1875

    Google Scholar 

  13. Ciccarese M, Casu D, Wong FK, Faedda R, Arvidsson S, Tonolo G, Luthman H, Satta A (2001) Identification of a new mutation in the α4(IV) collagen gene in a family with autosomal dominant Alport syndrome and hypercholesterolaemia. Nephrol Dial Transpl 16:2008–2012

    Google Scholar 

  14. Antignac C, Heidet L (1996) Mutations in Alport syndrome associated with diffuse esophageal leiomyomatosis. Contrib Nephrol 117:172–182

    Google Scholar 

  15. Antignac C, Zhou J, Sanak M, Cochat P, Roussel B, Deschenes G, Gros F, Knebelmann B, Hors-Cayla M-C, Tryggvason K, Gubler M-C (1992) Alport syndrome and diffuse leiomyomatosis: Deletions in the 5’ end of the COL4A5 gene. Kidney Int 42:1178–1183

    Google Scholar 

  16. Zhou J, Mochizuki T, Smeets H, Antignac C, Laurila P, de Paepe A, Tryggvason K, Reeders ST (1993) Deletion of the paired α5(IV) and α6(IV) collagen genes in inherited smooth muscle tumors. Science 261:1167–1169

    Google Scholar 

  17. Heidet L, Dahan K, Zhou J, Xu Z, Cochat P, Gould JDM, Leppig KA, Proesmans W, Guyot C, Guillot M, Roussel B, Tryggvason K, Grunfeld JP, Gubler MC, Antignac C (1995) Deletions of both α5(IV) and α6(IV) collagen genes in Alport syndrome and in Alport syndrome associated with smooth muscle tumors. Hum Mol Genet 4:99-108

    Google Scholar 

  18. Heidet L, Cohen-Solal L, Boye E, Thorner P, Kemper MJ, David A, Larget Piet L, Zhou J, Flinter F, Zhang X, Gubler MC, Antignac C (1997) Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region. Cytogenet Cell Genet 78:240–246

    Google Scholar 

  19. Segal Y, Peissel B, Renieri A, de Marchi M, Ballabio A, Pei Y, Zhou J (1999) LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. Am J Hum Genet 64:62–29

    Google Scholar 

  20. Peissel B, Geng L, Kalluri R, Kashtan C, Rennke HG, Gallo GR, Yoshioka K, Sun MJ, Hudson BG, Neilson EG, Zhou J (1995) Comparative distribution of the α1(IV), α5(IV) and α6(IV) collagen chains in normal human adult and fetal tissues and in kidneys from X-linked Alport syndrome patients. J Clin Invest 96:1948–1957

    Google Scholar 

  21. Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y, Makino H, Kagawa M, Sado Y, Kashtan CE (1994) Type IV Collagen α5 chain: normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. Am J Pathol 144:986–996

    Google Scholar 

  22. Cheong HI, Kashtan CE, Kim Y, Kleppel MM, Michael AF (1994) Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome. Lab Invest 70:553–557

    Google Scholar 

  23. Cosgrove D, Kornak JM, Samuelson G (1996) Expression of basement membrane type IV collagen chains during postnatal development in the murine cochlea. Hearing Res 100:21–32

    Google Scholar 

  24. Gubler MC, Knebelmann B, Beziau A, Broyer M, Pirson Y, Haddoum F, Kleppel MM, Antignac C (1995) Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Kidney Int 47:1142–1147

    Google Scholar 

  25. Grunfeld JP (2000) Contemporary diagnostic approach in Alport’s syndrome. Ren Fail 22:759–763

    Google Scholar 

  26. Nakanishi K, Yoshikawa N, Iijima K, Kitagawa K, Nakamura H, Ito H, Yoshioka K, Kagawa M, Sado Y (1994) Immunohistochemical study of α1–5 chains of type IV collagen in hereditary nephritis. Kidney Int 46:1413–1421

    Google Scholar 

  27. van der Loop FTL, Monnens LAH, Schroder CH, Lemmink HH, Breuning MH, Timmer EDJ, Smeets HJM (1999) Identification of COL4A5 defects in Alport syndrome by immunochemistry of skin. Kidney Int 55:1217–1224

    Google Scholar 

  28. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer K-O, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649–657

    Google Scholar 

  29. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2003) X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to to 195 families: a “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol 14:2603–2610.

    Google Scholar 

  30. Grunfeld J-P, Noel LH, Hafez S, Droz D (1985) Renal prognosis in women with hereditary nephritis. Clin Nephrol 23:267–271

    Google Scholar 

  31. Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, Samuelson GC (1996) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10:2981–2992

    Google Scholar 

  32. Hood JC, Savige J, Seymour AE, Dowling J, Martinello P, Colville D, Sinclair R, Naito I, Jennings G, Huxtable C (2000) Ultrastructural appearance of renal and other basement membranes in the Bull terrier model of autosomal dominant hereditary nephritis. Am J Kid Dis 36:378–391

    Google Scholar 

  33. Lees G, Helman RG, Kashtan CE, Michael AF, Homco LD, Millichamp NJ, Camacho ZT, Templeton JW, Ninomiya Y, Sado Y, Kim Y (1999) A new form of X-linked dominant hereditary nephritis in dogs. Am J Vet Res 60:373–383

    Google Scholar 

  34. Lees G, Helman RG, Kashtan CE, Michael AF, Homco LD, Millichamp NJ, Ninomiya Y, Sado Y, Kim Y (1998) A model of autosomal recessive Alport syndrome in English cocker spaniel dogs. Kidney Int 54:706–719

    Google Scholar 

  35. Lu W, Phillips CL, Killen PD, Hlaing T, Harrison WR, Elder FFB, Miner JH, Overbeek P, Meisler MH (1999) Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. Genomics 61:113–124

    Google Scholar 

  36. Miner JJ, Sanes JR (1996) Molecular and functional defects in kidneys of mice lacking collagen α3(IV): implications for Alport syndrome. J Cell Biol 135:1403–1413

    Google Scholar 

  37. Zheng K, Thorner PS, Marrano P, Baumal R, McInnes RR (1994) Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the α5 chain of collagentype IV. Proc Natl Acad Sci USA 91:3989–3993

    Google Scholar 

  38. Andrews KL, Mudd JL, Li C, Miner JH (2002) Quantitative trait loci influence renal disease progression in a mouse model of Alport syndrome. Am J Pathol 160:721–730

    Google Scholar 

  39. Kashtan CE, Gubler MC, Sisson-Ross S, Mauer M (1998) Chronology of renal scarring in males with Alport syndrome. Pediatr Nephrol 12:269–274

    Google Scholar 

  40. Heikkila P, Parpala T, Lukkarinen O, Weber M, Tryggvason K (1996) Adenovirus-mediated gene transfer into kidney glomeruli using an ex vivo and in vivo kidney perfusion system—first step towards gene therapy of Alport syndrome. Gene Therapy 3:21–27

    Google Scholar 

  41. Tryggvason K, Heikkila P, Pettersson E, Tibell A, Throner P (1997) Can Alport syndrome be treated by gene therapy? Kidney Int 52:1493–1499

    Google Scholar 

  42. Parpala-Sparman t, Lukkarinen O, Heikkila P, Tryggvason K (1999) A novel surgical organ perfusion method for effective ex vivo and in vivo gene transfer into renal glomerular cells. Urol Res 27:97–102

    Google Scholar 

  43. Harvey SJ, Zheng K, Jefferson B, Moak P, Sado Y, Naito I, Ninomiya Y, Jacobs R, Thorner PS (2003) Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo expression of the alpha 6(IV) collagen chain in a canine model of Alport syndrome. Am J Pathol 162:873–875

    Google Scholar 

  44. Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, Ghiggeri GM, Ravazzolo R, Savino M, Del Vecchio M, d’Apolito M, Iolascon A, Zelante LL, Savoia A, Balduini CL, Noris P, Magrini U, Belletti S, Heath KE, Babcock M, Glucksman MJ, Aliprandis E, Bizzaro N, Desnick RJ, Martignetti JA (2000) Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet 26:103–105

    Google Scholar 

  45. Seri M, Savino M, Bordo D, Cusano R, Rocca B, Meloni I, Di Bari F, Koivisto PA, Bolognesi M, Ghiggeri GM, Landolfi R, Balduini CL, Zelante L, Ravazzolo R, Renieri A, Savoia A (2002) Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene. Hum Genet 110:182–186

    Google Scholar 

  46. Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A (2003) MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore) 82:203–215

    Google Scholar 

  47. Arrondel C, Vodovar N, Knebelmann B, Grunfeld JP, Gubler MC, Antignac C, Heidet L (2002) Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndrome. J Am Soc Npehrol 13:65–74

    Google Scholar 

  48. Dische FE, Anderson VER, Keane SJ, Taube D, Bewick M, Parsons V (1990) Incidence of thin membrane nephropathy: morphometric investigation of a population sample. J Clin Pathol 43:457–460

    Google Scholar 

  49. Gubler M, Levy M, Broyer M, Naizot C, Gonzales G, Perrin D, Habib R (1981) Alport’s syndrome: a report of 58 cases and a review of the literature. Am J Med 70:493–505

    Google Scholar 

  50. Liapis H, Foster K, Miner JH (2002) Red cell traverse through thin glomerular basement membrane. Kidney Int 61:762–763.

    Google Scholar 

  51. Kashtan CE, Kim Y (1992) Distribution of the α1 and α2 chains of collagen IV and of collagens V and VI in Alport syndrome. Kidney Int 42:115–126

    Google Scholar 

  52. Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG (1997) 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

    Google Scholar 

  53. Harvey SJ, Zheng K, Sado Y, Naito I, Ninomiya Y, Jacobs RM, Hudson BG, Thorner PS (1998) Role of distinct type IV collagen networks in glomerular development and function. Kidney Int 54:1857–1866

    Google Scholar 

  54. Kashtan CE, Kim Y, Lees GE, Thorner PS, Virtanen I, Miner JH (2001) Abnormal glomerular basement membrane laminins in murine, canine, and human Alport sydnrome: aberrant laminin alpha2 deposition is species independent. J Am Soc Nephrol 12:252–260

    Google Scholar 

  55. Abrahamson DR, Prettyman AC, Robert B, St John PL (2003) Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 63:826–834

    Google Scholar 

  56. St John PL, Abrahamson DR (2001) Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and −11 chains. Kidney Int 60:1037-1046

    Google Scholar 

  57. Sayers R, Kalluri R, Rodgers KD, Shield CF, Meehan DT, Cosgrove D (1999) Role for transforming growth factor-beta 1 in Alport renal disease progression. Kidney Int 56:1662–1673

    Google Scholar 

  58. Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, Gardner H, Kotelianski V, Gotwals P, Amatucci A, Kalluri R (2000) Integrin alpha1beta1 and transforming growth factor-beta 1 play distinct roles in Alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol 157:1649–1659

    Google Scholar 

  59. Rao VH, Lees GH, Kashtan CE, Nemori R, Singh RK, Meehan DT, Rodgers K, Berridge BR, Bhattacharya G, Cosgrove D (2003) Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS). Kidney Int 63:1736–1748

    Google Scholar 

  60. Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285:F1060–1067

    Google Scholar 

  61. Nieuwhof CM, de Heer F, de Leeuw P, van Breda Vriesman PJ (1997) Thin GBM nephropathy: premature glomerular obsolescence is associated with hypertension and late onset renal failure. Kidney Int 51:1596–1601

    Google Scholar 

  62. van Paassen P, van Breda Vriesman PJ, van Rie H, Tervaert JW (2004) Signs and symptoms of thin basement membrane nephropathy: a prospective regional study on primary glomerular disease-The Limburg Renal Registry. Kidney Int 66:909–913

    Google Scholar 

  63. Merchant SN, Burgess BJ, Adams JC, Kashtan CE, Gregory MC, Santi PA, Colvin R, Collins B, Nadol JB Jr (2004) Temporal bone histopathology in Alport syndrome. Laryngoscope 114:1609–1618

    Google Scholar 

  64. Rhys C, Snyers B, Pirson Y (1997) Recurrent corneal erosion associated with Alport’s syndrome. Kidney Int 52:208–211

    Google Scholar 

  65. Colville DJ, Savige J (1997) Alport syndrome: a review of the ocular manifestations. Ophthalmic Genet 18:161–173

    Google Scholar 

  66. Colville D, Savige J, Morfis M, Ellis J, Kerr P, Agar J, Fasset R (1997) Ocular manifestations of autosomal recessive Alport syndrome. Ophthalmic Genet 18:119–128

    Google Scholar 

  67. Streeten BW, Robinson MR, Wallace R, Jones DB (1987) Lens capsule abnormalities in Alport’s syndrome. Arch Ophthalmol 105:1693–1697

    Google Scholar 

  68. Adler L, Mathew R, Futterweit S, Frank R, Gauthier BG, Kashtan CE, Trachtman H (2002) Angiotensin converting enzyme inhibitor therapy in children with Alport syndrome: effect on urinary albumin, TGF-beta, and nitrite excretion. BMC Nephrol 3:2

    Google Scholar 

  69. Cohen EP, Lemann J (1996) In hereditary nephritis angiotensin-converting enzyme inhibition decreases proteinuria and may slow the rate of progression. Am J Kid Dis 27:199–203

    Google Scholar 

  70. Proesmans W, Knockaert H, Trouet D (2000) Enalapril in paediatric patients with Alport syndrome: 2 years’ experience. Eur J Pediatr 159:430–433

    Google Scholar 

  71. Proesmans W, Van Dyck M (2004) Enalapril in children with Alport syndrome. Pediatr Nephrol 19:271–275

    Google Scholar 

  72. Gross O, Schulze-Lohoff E, Koepke ML, Beirowski B, Addicks K, Bloch W, Smyth N, Weber M (2004) Antifibrotic, nephroprotective potential of ACE inhibitor vs. AT1 antagonist in a murine model of renal fibrosis. Nephrol Dial Transplant 19:1716–1723

    Google Scholar 

  73. Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446

    Google Scholar 

  74. Grodecki KM, Gains MJ, Baumal R, Osmond DH, Cotter BV, V. E., Jacobs RM (1997) Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme inhibitor. J Comp Pathol 117:209–225

    Google Scholar 

  75. Callis L, Vila A, Carrera M, Nieto J (1999) Long-term effects of cyclosporine A in Alport’s syndrome. Kidney Int 55:1051–1056

    Google Scholar 

  76. Callis L, Vila A, Nieto J, Fortuny G (1992) Effect of cyclosporin A on proteinuria in patients with Alport’s syndrome. Pediatr Nephrol 6:140–144

    Google Scholar 

  77. Charbit M, Dechaux M, Gagnadoux M, Grunfeld J, Niaudet P (2003) Cyclosporine A therapy in Alport syndrome. J Am Soc Nephrol 14:111A

    Google Scholar 

  78. Massella L, Rizzoni G (2001) Cyclosporine treatment of young patients with Alport syndrome and proteinuria. J Am Soc Nephrol 12:116A

    Google Scholar 

  79. Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, Thorner PS (2003) Cyclosporine A slows the progressive renal disease of Alport syndrome (X-linked hereditary nephritis): results from a canine model. J Am Soc Nephrol 14:690–698

    Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health (RO1 DK57676).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clifford E. Kashtan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kashtan, C.E. Familial hematurias: what we know and what we don’t. Pediatr Nephrol 20, 1027–1035 (2005). https://doi.org/10.1007/s00467-005-1859-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-005-1859-z

Keywords

Navigation