eMedicine Specialties > Nephrology > Hereditary Kidney Disorders

Alport Syndrome: Follow-up

Author: Ramesh Saxena, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center
Contributor Information and Disclosures

Updated: Sep 9, 2008

Follow-up

Further Outpatient Care

  • Control the patient's blood pressure.
  • Administer ACE inhibitors or ARBs to control proteinuria.
  • Monitor renal function test results and proteinuria (24-h urinary protein and creatinine). Check 24-hour urinary protein, creatinine, and serum chemistry on an annual basis in those patients without renal insufficiency or those with mild renal insufficiency, every 6 months in those patients with moderate renal insufficiency, and every 1-3 months in those patients with advanced renal failure.

Inpatient & Outpatient Medications

  • Administer ACE inhibitors or ARBs to control proteinuria and hypertension.

Transfer

  • Transfer to a dialysis facility when the patient develops ESRD.

Complications

  • Progression of renal failure
    • The risk of progression of renal failure is highest among males with XLAS and in both males and females with ARAS. ESRD develops in virtually all males with XLAS. Approximately 90% of patients develop ESRD by age 40 years. According to the age at ESRD, XLAS arbitrarily is either the juvenile type or the adult type with a cut off at age 30 years. The juvenile type is encountered in 75% of kindreds. Renal prognosis depends on the kind of mutation. The probability of ESRD in people younger than 30 years is significantly higher (90%) in patients with large rearrangement of the COL4A5 gene compared to those with minor mutations (50-70%). Furthermore, the rate of progression of renal disease is fairly constant among patients within a particular family but shows significant variability between different families.
    • The prognosis in females with XLAS is usually benign, and they rarely develop ESRD. The reported probability of developing ESRD in these patients is 12% by age 40 years and 30% by age 60 years. Risk factors for progression to ESRD are episodes of gross hematuria in childhood, nephrotic range proteinuria, and diffuse GBM thickening on examination with an electron microscope.
  • Hematologic disorders: Several reports describe families with hereditary nephritis associated with deafness, megathrombocytopenia (giant platelets), and, in some families, granulocyte abnormalities. Clinical features include bleeding tendency, macrothrombocytopenia, abnormalities of platelet aggregation (ie, Epstein-Barr syndrome), and, occasionally, neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechner syndrome). In most patients, the autosomal dominant pattern of inheritance is observed. In only 2 reports, focal thickening, splitting, or lamellation of the GBM was identified. The basement membrane of these patients showed normal expression of a chain of type IV collagen. So far, the genetic loci involved remain unknown.

Prognosis

  • Renal prognosis depends on the kind of mutation. Approximately 90% of patients with Alport syndrome develop ESRD by age 40 years. The probability of ESRD in people younger than 30 years is significantly higher in patients with a large rearrangement of the COL4A5 gene compared to those with minor mutations. Prognosis in females with XLAS is usually benign, with only 12% developing ESRD by age 40 years and 30% by age 60 years.

Patient Education

  • Provide pre-ESRD education to discuss various options and issues regarding renal replacement therapy (eg, dialysis, transplantation).
  • Arrange dietary counseling for patients approaching ESRD.
  • Avoid administering nephrotoxins in these patients, including over-the-counter nonsteroidal analgesic agents.
  • For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.

Miscellaneous

Medicolegal Pitfalls

  • Erroneous determination of the mode of inheritance of Alport syndrome can lead to potential adverse consequences such as unnecessary medical termination of pregnancy. In these situations, a firm diagnosis and mode of inheritance of Alport syndrome by genetic analysis is needed to provide information essential for determining prognosis and guiding genetic counseling. This also underscores the need for trained medical geneticists to interpret complex inheritance modes in clinical situations where genetic heterogeneity exists in human Mendelian diseases.

Special Concerns

  • Anti-GBM disease in patients with Alport syndrome who receive a renal transplant
    • Approximately 3-5% of patients with Alport syndrome who received a renal transplant develop anti-GBM nephritis. These patients possess circulating anti-GBM antibodies. Antibodies in patients with ARAS predominantly bind to the alpha-3 and alpha-4 (IV) chain of type IV collagen, whereas most antibodies in patients with XLAS bind to the alpha-5 (IV) chain of type IV collagen.2,3 These antigens are not expressed in the native kidneys of patients with Alport syndrome but are present in the transplanted kidneys and are recognized as a foreign antigen by the recipient's immune system.
    • Only a few patients develop anti-GBM disease after transplantation; the cause remains unclear. At present, the only way to determine whether a patient with Alport syndrome will develop posttransplant anti-GBM nephritis is to perform the transplant; however, certain patients are at very low risk for developing posttransplant anti-GBM nephritis, including patients with normal hearing, patients with late progression to ESRD, or females with XLAS.
    • Posttransplant anti-GBM nephritis usually develops within the first year of the transplant. Patients typically develop rapidly progressive glomerulonephritis with findings on kidney biopsy showing crescentic glomerulonephritis and linear immune deposits along the GBM. Unlike de novo anti-GBM nephritis, pulmonary hemorrhage is never observed in posttransplant anti-GBM nephritis in patients with Alport syndrome because the patient's lung tissue does not contain the Goodpasture antigen (NC1 component of the alpha-3 [IV] chain). Treatment with plasmapheresis and cyclophosphamide is usually unsuccessful, and most patients lose the allograft.4
    • Retransplantation in most patients results in recurrence of anti-GBM nephritis despite the absence of detectable circulating anti-GBM antibodies before transplantation. Because of excellent graft survival rates and a very low incidence of clinical anti-GBM disease, renal transplantation is not contraindicated in patients with Alport syndrome; however, in patients who have already lost an allograft from posttransplant anti-GBM nephritis, the optimal management is uncertain because of the high likelihood of recurrence and subsequent allograft loss.
 


More on Alport Syndrome

Overview: Alport Syndrome
Differential Diagnoses & Workup: Alport Syndrome
Treatment & Medication: Alport Syndrome
Follow-up: Alport Syndrome
Multimedia: Alport Syndrome
References
[ CLOSE WINDOW ]

References

  1. Citirik M, Batman C, Men G, et al. Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome. Clin Exp Optom. Sep 2007;90(5):367-70. [Medline].

  2. Wang XP, Fogo AB, Colon S, et al. Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen. J Am Soc Nephrol. Dec 2005;16(12):3563-71. [Medline].

  3. Borza DB. Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis. Nephron Exp Nephrol. 2007;106(2):e37-43. [Medline]. [Full Text].

  4. Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol. Sep 1998;9(9):1736-50. [Medline].

  5. Alport AC. Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1927;1:504-6.

  6. Brainwood D, Kashtan C, Gubler MC, et al. Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation. Kidney Int. Mar 1998;53(3):762-6. [Medline].

  7. Callis L, Vila A, Carrera M, et al. Long-term effects of cyclosporine A in Alport's syndrome. Kidney Int. Mar 1999;55(3):1051-6. [Medline].

  8. Charytan D, MacDonald B, Sugimoto H, et al. An unusual case of pulmonary-renal syndrome associated with defects in type IV collagen composition and anti-glomerular basement membrane autoantibodies. Am J Kidney Dis. Apr 2005;45(4):743-8. [Medline].

  9. Colville D, Dagher H, Miach P, et al. Ocular clues to the nature of disease causing end-stage renal failure. Nephrol Dial Transplant. Mar 2000;15(3):429-32. [Medline].

  10. Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. Dec 1997;18(4):161-73. [Medline].

  11. Flinter F. Alport's syndrome. J Med Genet. Apr 1997;34(4):326-30. [Medline].

  12. Gunwar S, Ballester F, Noelken ME, et al. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem. Apr 10 1998;273(15):8767-75. [Medline].

  13. Harvey SJ, Zheng K, Jefferson B, et al. 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. Mar 2003;162(3):873-85. [Medline].

  14. Harvey SJ, Zheng K, Sado Y, et al. Role of distinct type IV collagen networks in glomerular development and function. Kidney Int. Dec 1998;54(6):1857-66. [Medline].

  15. Heidet L, Cai Y, Guicharnaud L, et al. Glomerular expression of type IV collagen chains in normal and X-linked Alport syndrome kidneys. Am J Pathol. Jun 2000;156(6):1901-10. [Medline].

  16. Heikkilä P, Tryggvason K, Thorner P. Animal models of Alport syndrome: advancing the prospects for effective human gene therapy. Exp Nephrol. Jan-Feb 2000;8(1):1-7. [Medline].

  17. Hudson BG. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J Am Soc Nephrol. Oct 2004;15(10):2514-27. [Medline].

  18. Hudson BG, Wieslander J, Wisdom BJ Jr, et al. Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab Invest. Sep 1989;61(3):256-69. [Medline].

  19. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol. Apr 2000;11(4):649-57. [Medline].

  20. Jefferson JA, Lemmink HH, Hughes AE, et al. Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant. Aug 1997;12(8):1595-9. [Medline].

  21. Kalluri R, Shield CF, Todd P, et al. 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. May 15 1997;99(10):2470-8. [Medline].

  22. Kalluri R, Torre A, Shield CF 3rd, et al. Identification of alpha3, alpha4, and alpha5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation. Feb 27 2000;69(4):679-83. [Medline].

  23. Kashtan CE. Alport syndrome: is diagnosis only skin-deep?. Kidney Int. Apr 1999;55(4):1575-6. [Medline].

  24. Kashtan CE. Renal transplantation in patients with Alport syndrome. Pediatr Transplant. Sep 2006;10(6):651-7. [Medline].

  25. Kleppel MM, Fan WW, Cheong HI, et al. Immunochemical studies of the Alport antigen. Kidney Int. Jun 1992;41(6):1629-37. [Medline].

  26. Lemmink HH, Schroder CH, Monnens LA, et al. The clinical spectrum of type IV collagen mutations. Hum Mutat. 1997;9(6):477-99. [Medline].

  27. Mazzarella V, Splendiani G, Tozzo C, et al. Renal transplantation in patients with hereditary kidney disease: our experience. Contrib Nephrol. 1997;122:203-6. [Medline].

  28. Meleg-Smith S, Magliato S, Cheles M, et al. X-linked Alport syndrome in females. Hum Pathol. Apr 1998;29(4):404-8. [Medline].

  29. Miner JH. Alport syndrome with diffuse leiomyomatosis. When and when not?. Am J Pathol. Jun 1999;154(6):1633-5. [Medline].

  30. Nomura S, Naito I, Fukushima T, et al. Molecular genetic and immunohistochemical study of autosomal recessive Alport's syndrome. Am J Kidney Dis. Jun 1998;31(6):E4. [Medline].

  31. Pirson Y. Making the diagnosis of Alport's syndrome. Kidney Int. Aug 1999;56(2):760-75. [Medline].

  32. Plant KE, Green PM, Vetrie D, et al. Detection of mutations in COL4A5 in patients with Alport syndrome. Hum Mutat. 1999;13(2):124-32. [Medline].

  33. Sado Y, Kagawa M, Naito I, et al. Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem. May 1998;123(5):767-76. [Medline].

  34. Swann PG, Patel S. Lenticular changes in Alport's syndrome. Clin Exp Optom. Jan 2005;88(1):53-4. [Medline].

  35. Timpl R, Wiedemann H, van Delden V, et al. A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem. Nov 1981;120(2):203-11. [Medline].

  36. van der Loop FT, Heidet L, Timmer ED, et al. Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int. Nov 2000;58(5):1870-5. [Medline].

  37. van der Loop FT, Monnens LA, Schroder CH, et al. Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin. Kidney Int. Apr 1999;55(4):1217-24. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

Alport syndrome, kidney failure, renal failure, AS, hereditary nephritis, deafness, hematuria, type IV collagen, end-stage renal disease, ESRD, glomerular basement membrane, GBM, tubular basement membrane, TBM, autosomal dominant Alport syndrome, ADAS, autosomal recessive Alport syndrome, ARAS, X-linked Alport syndrome, XLAS, leiomyomatosis, anterior lenticonus, dot-and-fleck retinopathy, proteinuria

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Ramesh Saxena, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center
Ramesh Saxena, MD, PhD is a member of the following medical societies: American Medical Association, American Society of Nephrology, and International Society of Nephrology
Disclosure: e-medicine Honoraria authoring review articles

Medical Editor

Frank C Brosius III, MD, Nephrology Program Director, Department of Internal Medicine, Division of Nephrology, Professor of Internal Medicine and Physiology, University of Michigan School of Medicine
Frank C Brosius III, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, American Society of Nephrology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Roche Honoraria Consulting

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.