Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

Tamehito Onoe,Akihiro Kuma,Shoichiro Daimon,Junko Imura,Yoshifumi Ubara,Tadashi Konoshita,Kiyoaki Ito,Michihiro Mitobe,Kazunori Yamada,Nao Kishimoto,Ichiro Mizushima,Takayasu Mori,Akira Iguchi,Hiroaki Tsuruta,Mitsuhiro Kawano,Satoshi Hara,Takeshi Zoshima,Hiroaki Muramoto,Maki Shimizu

doi:10.1186/s12882-020-02169-x

Abstract

BackgroundAutosomal 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.MethodsThirteen 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.ResultsInterstitial 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.ConclusionsMassively 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.

Highlights

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations
Autosomal dominant tubulointerstitial kidney disease caused by UMOD gene mutation (ADTKD-UMOD) used to be named medullary cystic kidney disease type2 (MCKD2; MIM 603860), glomerulocystic kidney disease (GCKD), familial juvenile hyperuricemic nephropathy (FJHN; MIM 162000) or uromodulin kidney disease (UKD) [1, 4]
Two different missense mutations were detected in one patient

Summary

Introduction

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. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic disease, whose characteristics include progressive kidney injury, interstitial fibrosis and tubular atrophy. Autosomal dominant tubulointerstitial kidney disease caused by UMOD gene mutation (ADTKD-UMOD) used to be named medullary cystic kidney disease type (MCKD2; MIM 603860), glomerulocystic kidney disease (GCKD), familial juvenile hyperuricemic nephropathy (FJHN; MIM 162000) or uromodulin kidney disease (UKD) [1, 4]. Besides common features of ADTKD such as autosomal dominant trait, progressive kidney injury and interstitial tubulopathy, early onset of hyperuricemia and gout are well-known characteristics of ADTKD-UMOD

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