Tamehito Onoe1, Satoshi Hara1, Kazunori Yamada2, Takeshi Zoshima1, Ichiro Mizushima1, Kiyoaki Ito1, Takayasu Mori3, Shoichiro Daimon4, Hiroaki Muramoto5, Maki Shimizu6, Akira Iguchi7, Akihiro Kuma8, Yoshifumi Ubara9, Michihiro Mitobe10, Hiroaki Tsuruta11, Nao Kishimoto12, Junko Imura13, Tadashi Konoshita14, Mitsuhiro Kawano15. 1. Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan. 2. Kanazawa Medical University, Department of Hematology and Immunology, Uchinada-Machi, Ishikawa, Japan. 3. Department of Nephrology, Tokyo Medical and Dental University, Yushima, Tokyo, Japan. 4. Department of Nephrology, Daimon Clinic for Internal Medicine, Nephrology and Dialysis, Nonoichi, Ishikawa, Japan. 5. Department of Internal Medicine, Japan Health Care Organization Kanazawa Hospital, Kanazawa, Ishikawa, Japan. 6. Shimizu Children's Clinic, Takamatsu, Kagawa, Japan. 7. Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan. 8. University of Occupational and Environmental Health School of Medicine, Second Department of Internal Medicine, Kitakyusyu, Fukuoka, Japan. 9. Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Toranomon, Tokyo, Japan. 10. Department of Nephrology, Kameda Medical Center, Kamogawa, Chiba, Japan. 11. Nagahama City Hospital, Department of Nephrology and Metabolism, Nagahama, Shiga, Japan. 12. Osaka Saiseikai Izuo Hospital, Department of Nephrology, Osaka-city, Osaka, Japan. 13. Imura Clinic, Department of Nephrology and Dialysis, Hakusan-city, Ishikawa, Japan. 14. Third Department of Internal Medicine, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, Japan. 15. Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan. mk0920@mac.com.
Abstract
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.
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