eMedicine Specialties > Nephrology > Hereditary Kidney Disorders

Alport Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Other Problems to Be Considered

Immunoglobulin A nephropathy

Thin GBM disease

Rarely, pulmonary-renal syndrome with antibodies directed against the alpha-2 NC1 domain of type IV collagen may be a manifestation of X-linked Alport syndrome of thin GBM disease.

Workup

Laboratory Studies

  • Urinalysis: Urinary dipstick test and a 24-hour urine specimen for protein and creatinine should be performed to detect hematuria and proteinuria. Also, urinary sediment should be analyzed by microscope to detect dysmorphic red blood cells and red blood cell casts.
  • Hematuria: Urinary sediment frequently reveals dysmorphic red blood cells and red blood cell casts. Whenever possible, screening of the first-degree relatives for microscopic hematuria of glomerular origin should be performed.
  • Proteinuria: Proteinuria is usually absent in early childhood, but it eventually develops. Proteinuria usually progresses with age and can be in the nephrotic range in as many as 30% of patients.

Imaging Studies

  • Renal ultrasound: In early stages, a renal ultrasound shows healthy-sized kidneys; however, with advancing renal failure, the kidneys become smaller and echogenic.

Other Tests

  • Genetic analysis: If diagnosis remains doubtful after skin or kidney biopsy, screening for genetic mutations may be considered; however, the screening for COL4A3, COL4A4, and COL4A5 mutations is expensive, time consuming, extremely difficult, and not widely available. Moreover, the current detection rate of COL4A5 mutations in relatives with Alport syndrome is only about 50%; thus, for now, genetic analysis should be restricted for prenatal diagnosis or when uncertainty about diagnosis or mode of transmission of Alport syndrome exists.

Procedures

  • Biopsy: Obtain tissue from the kidneys and skin to reveal ultrastructural abnormalities.
    • Skin biopsy is less invasive than renal biopsy and should be obtained first.
    • Kidney biopsy most often provides the diagnosis if it is not established by skin biopsy.

Histologic Findings

The absence of alpha-5 (IV) chains of type IV collagen in the epidermal basement membrane on skin biopsy is diagnostic of XLAS. In such cases, kidney biopsy is not necessary for diagnosis; however, the absence of alpha-5 (IV) chains in the epidermal basement membrane is observed in only 80% of males with XLAS. Therefore, the presence of alpha-5 (IV) chains in the epidermal basement membrane does not rule out the diagnosis of XLAS; moreover, the alpha-5 (IV) chain is expressed in the epidermal basement membrane in autosomal recessive disease. Thus, the presence of alpha-5 (IV) chain in the epidermal basement membrane indicates a mutation in the alpha-5 (IV) chain that permits its expression in skin but not in the kidney in XLAS, ARAS, or another disorder.

Findings on light microscopy of kidney biopsy specimens contribute little toward the diagnosis. The findings are nonspecific and include segmental and focal glomerulosclerosis, tubular atrophy, interstitial fibrosis, and infiltration by lymphocytes and plasma cells with clusters of foam cells of uncertain origin. Findings on standard immunofluorescence studies are usually negative.

Monoclonal antibodies directed against alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen can be used to evaluate the GBM for the presence or absence of these chains. The absence of these chains from the GBM is diagnostic of Alport syndrome and has not been described in any other condition. In addition, renal expression of type IV collagen alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains can differentiate XLAS and ARAS. In most patients with XLAS, alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains are absent from the GBM and distal TBM. On the other hand, in ARAS, no expression of alpha-3 (IV) and alpha-4 (IV) chains exists, while the alpha-5 (IV) chain is expressed in the GBM and distal TBM; however, normal staining of the GBM for alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains does not rule out the diagnosis of Alport syndrome.

Electron microscopy reveals diffuse thickening and splitting of the basement membrane in 60-90% of patients. Diffuse thinning is observed in some patients with Alport syndrome. A normal ultrastructure of the GBM makes a diagnosis of Alport syndrome highly unlikely.

More on Alport Syndrome

Overview: Alport Syndrome
Differential Diagnoses & Workup: Alport Syndrome
Treatment & Medication: Alport Syndrome
Follow-up: Alport Syndrome
Multimedia: Alport Syndrome
References
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References

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Further Reading

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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

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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.

 
 
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