Published papers

The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans. [Figure not available: see fulltext.].

© 2018 The Japan Society of Hepatology Aim: Elastic fiber deposition is a cause of irreversibility of liver fibrosis. However, to date, its relevance to clinical features has not yet been clarified. This study aimed to clarify the correlation between non-invasive markers of fibrosis and fiber quantity, including elastic fiber, obtained from computational analysis. Methods: This retrospective study included 270 patients evaluated by non-invasive liver fibrosis assessment prior to liver biopsy. Of these patients, 95 underwent magnetic resonance elastography (MRE) and 244 were assessed with Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + -M2BP). Using whole-slide imaging of Elastica van Gieson-stained liver biopsy sections, the quantity of collagen, elastin, and total fiber (elastin + collagen) was determined. Results: The total fiber quantity showed significant linear correlation with fibrosis stage F0–F4. Collagen fiber quantity increased from stage F0 to F4, whereas elastic fiber quantity increased significantly only from stage F2 to F3. Spearman's rank correlation test revealed that non-invasive liver fibrosis assessment significantly correlates with each fiber quantity, including correlation between total fiber quantity and the Fibrosis-4 (FIB-4) index (r = 0.361, P < 0.001), WFA + -M2BP values (r = 0.404, P < 0.001), and liver stiffness value by MRE (r = 0.615, P < 0.001). Receiver operating characteristic (ROC) curve analyses revealed that the area under ROC for predicting higher elastic fiber (>3.6%) is 0.731 by FIB-4 index, 0.716 by WFA + -M2BP, and 0.822 by liver stiffness by MRE. Conclusion: Liver fibrosis correlates with fiber quantity through non-invasive assessment regardless of fiber type, including elastic fiber. Moreover, MRE is useful for predicting high amounts of elastic fiber.

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomeg

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) is a major cause of rapidly progressive glomerulonephritis (RPGN). ANCA-associated CGN is generally classified into pauci-immune RPGN, in which there are few or no immune complexes. CASE PRESENTATION: A 78-year-old man presented with RPGN after a 7-year course of chronic proteinuria and hematuria with stable renal function. A blood examination showed a high titer of myeloperoxidase (MPO)-ANCA. A renal biopsy showed crescentic glomerulonephritis with abundant subepithelial, intramenbranous and subendothelial deposits by electron microscopy, leading to the diagnosis of ANCA-associated CGN superimposed on type 3 membranoproliferative glomerulonephritis (MPGN). CONCLUSIONS: This case is unique in that type 3 MPGN and MPO-ANCA-associated CGN coexisted, and no similar case has been reported to date. Because ANCA-associated CGN has a predilection for elderly individuals and primary type 3 MPGN is rarely seen in this age group, coincidental existence appears less likely. This case may confer valuable information regarding the link between immune complex and ANCA-associated CGN.

HE染色病理組織標本におけるコンピュータ診断支援の従来研究では、細胞核の形態的特徴を用いる場合が多いが、特に高分化がんあるいは早期がんの検出、診断においては核情報以上に組織構造が重要な役割を持っている。本発表では、肝細胞がんを対象として、これまでに我々が検討を行ってきた組織構造の特徴量をがんの識別に応用した基礎的な結果を報告する。具体的には、肝細胞索の層の厚さ、索構造の乱れ、肝細胞索ごとに算出したN/C比及び核密度などを画像から計測した結果、がんと非がんの間で有意差が認められた。さらに、これらの組織構造の特徴量を従来の細胞核の特徴量に加えることにより、がん識別の精度を向上する可能性が示された。本手法で用いた組織構造の特徴量は、病理組織標本のデジタルスライド画像から自動的に算出できるもので、定量的情報に基づくコンピュータ病理診断支援システムに有用なものと考えられる。(著者抄録)

HE染色肝病理標本における肝細胞がんの診断では、細胞核や細胞配列など様々な形態学的特徴が用いられる。これらの画像解析に関する研究としては、従来、細胞核に着目した研究が多く報告されているが、がんの診断には、核の情報だけでは不十分である。本研究では、細胞配列に基づく特徴量を定量化することで、がんの検出や、分化度分類等に応用することを提案する。正常な肝組織では、肝細胞は索状に配列し、整然とした小葉構造を形成しているが、がんでは、これらの配列に乱れが生じる。これは小領域で考えた場合、正常では肝細胞索同士が並行に近い関係にあり、一定の方向性を持つのに対し、がんでは、細胞索の方向に規則性が失われると考えられる。そこで本研究では、細胞索同士で相対的な角度を算出し、その分布に基づく特徴量を求めた。提案法により、肝細胞の索状配列の特徴を定量化することで、肝細胞がんの識別に利用できる可能性が得られた。(著者抄録)