Kidney Week

Abstract: TH-PO0582

Challenges in the Histopathologic Diagnosis of Autosomal Dominant Alport Syndrome: A Comparative Genotype-Based Study

Session Information

• Monogenic Kidney Diseases: Glomerular
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Manabe, Shun, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Shun Manabe, MD, PhD

• Seki, Momoko, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Momoko Seki

• Ushio, Yusuke, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Yusuke Ushio, MD, PhD

• Makabe, Shiho, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Shiho Makabe

• Kobayashi, Shizuka, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Shizuka Kobayashi, MD

• Ito, Naoko, Tokyo Women's Medical University, department of pathology, Tokyo, Shinjuku-ku, Japan

Naoko Ito, MD

• Kataoka, Hiroshi, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Hiroshi Kataoka

• Taneda, Sekiko, Tokyo Women's Medical University, department of pathology, Tokyo, Shinjuku-ku, Japan

Sekiko Taneda, MD, PhD

• Hoshino, Junichi, Tokyo Women's Medical University, department of nephrology, Shinjuku-ku, Tokyo, Japan

Junichi Hoshino, MD, PhD, MPH

Background

Recent advances have reshaped the understanding of hereditary nephritis with familial hematuria, including Alport syndrome and thin basement membrane disease (TBMD). Alport syndrome is now considered a spectrum: X-linked (XLAS), autosomal recessive (ARAS), female XLAS, and autosomal dominant (ADAS). While severe forms like XLAS (M) and ARAS have defined pathology—such as GBM lamellation and α5 collagen defects—the features of milder forms, especially ADAS, remain unclear. TBMD also overlaps genetically with ADAS, challenging its benign label. These findings highlight the limits of biopsy and the need for genetic testing.

Methods

We reviewed patients seen from January 2022 to December 2024 who underwent kidney biopsy and genetic testing (COL4A3, COL4A4, COL4A5) for glomerular hematuria with a family history suggestive of hereditary nephritis or TBMD. Clinical data, light microscopy, type IV collagen α2/α5 staining, electron microscopy, and genetic results were evaluated and compared using Fisher’s exact or chi-square test.

Results

Forty patients (28 female, mean age 49.4 ± 16.1 years) with persistent glomerular hematuria were included. Genetic testing identified 9 XLAS (4 males), 2 ARAS, 17 ADAS, and 12 without pathogenic variants. All underwent kidney biopsy (47 total), including repeats in six.
XLAS (M) and ARAS showed form cell infiltration, GBM lamellation, and absent or weakened α5 collagen staining. Female XLAS showed diffuse GBM thinning but no significant differences from Not AS. ADAS showed marked overlap with Not AS in all features, emphasizing the limited value of biopsy alone and the need for genetic testing in suspected ADAS.

Conclusion

XLAS (M) and ARAS showed characteristic features, including GBM lamellation and reduced or absent α5 collagen staining, aiding diagnosis when combined with clinical and genetic data. In contrast, ADAS showed findings similar to Not AS, underscoring the limited value of pathology alone and the need for genetic testing, particularly in suspected ADAS.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025a9e2vv7t