Published papers

OBJECTIVE: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. METHODS: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). RESULTS: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = -0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = -0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = -0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). CONCLUSION: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

A man in his 60s diagnosed with perihilar cholangiocarcinoma underwent radical surgery. CT on postoperative day 26 showed multiple liver metastases in the remnant liver that rapidly grew and spread to the entire liver. The patient died 70 days following surgery due to highly aggressive tumour progression. In the surgical specimen, the tumour at the margin was histologically identified as predominantly conventional adenocarcinoma, but a few components of the invasive carcinoma and liver metastasis exhibited significant nuclear atypia and rich cytoplasm. The autopsy revealed human chorionic gonadotropin (hCG)-positive multinucleated tumour cells like syncytiotrophoblast with haemorrhage at the metastatic sites in the liver, which finally diagnosed with cystic duct carcinoma with trophoblastic differentiation. hCG-positive carcinomas with trophoblastic differentiation generally carry poor prognoses. For those with significant nuclear atypia and rich cytoplasms with haemorrhage, additional immunostaining for hCG and progression to trophoblastic differentiation should be considered.

Background: Tubulointerstitial diseases arise from various etiologies, including infections, medications, autoimmune conditions, and systemic disorders. The histological presentation of the tubulointerstitium in renal biopsies can vary considerably. When tubulointerstitial alterations are identified through light microscopy, additional evaluation with immunofluorescence and electron microscopy may assist in diagnosis. This report describes two slowly progressive atypical cases of tubulointerstitial disease. Renal biopsy in both cases revealed tubular atrophy and interstitial fibrosis with limited inflammatory cell infiltration, along with polyclonal linear immunoglobulin G (IgG) staining pattern along the thickened tubular basement membrane (TBM) and distinctive electron-dense deposits. Case 1: Case presentation: A 65-year-old Japanese man with a history of chronic obstructive pulmonary disease, benign prostatic hyperplasia, and hypertension presented with anorexia and malaise 1 week prior to admission. Blood tests demonstrated marked renal impairment. Renal biopsy findings included relatively preserved glomeruli, widespread tubular atrophy, and significant interstitial fibrosis. Immunofluorescence showed linear deposition of IgG as well as kappa and lambda light chains along the TBM. Complement components C3 was also positive, and C1q were weakly positive. IgG subclass staining revealed positivity for IgG1, IgG2, and IgG4. Electron microscopy revealed electron-dense deposits within the TBM and on the epithelial side of the TBM, exhibiting a mottled and speckled appearance. Case 2: A 52-year-old Japanese man who had undergone allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia developed mild proteinuria and renal dysfunction 7 years after transplant. Renal biopsy indicated thrombotic microangiopathy, with glomeruli showing diffuse mesangial expansion and focal mesangiolysis. There was also diffuse TBM thickening and interstitial fibrosis with scattered cellular infiltration. Immunofluorescence demonstrated linear staining of polyclonal IgG and both light chains along the TBM. C3 was also positive while C1q was negative. IgG subclass staining revealed positivity for IgG1 and IgG4. Electron microscopy again identified electron-dense deposits within the reticulated TBM. Conclusions: These two cases demonstrated linear IgG immunofluorescence and distinctive electron-dense deposits in the TBM characterized by a mottled and speckled pattern. Although the underlying pathophysiological mechanisms remain unclear, further research is necessary to elucidate the nature of this form of tubulointerstitial disease.

Background: Although proteinuria is a key prognostic marker in immunoglobulin A nephropathy (IgAN), the optimal post-biopsy timing for its assessment remains uncertain, particularly given variability in treatment type and timing. Using longitudinal data from the Japan IgA Nephropathy Prospective Cohort Study (J-IGACS), we sought to identify the post-biopsy time point at which proteinuria most reliably predicts kidney outcomes. Methods: Proteinuria was assessed at baseline and at 6, 12, 18, and 24 months after biopsy. The primary outcome was defined as a ≥ 50% increase in serum creatinine or initiation of kidney replacement therapy in adults (≥ 20 years) and as a ≥ 25% decline in eGFR or initiation of kidney replacement therapy in patients aged < 20 years. Model performance was compared using the corrected Akaike Information Criterion. Results: Among 588 patients (median age 38 years; mean eGFR 76.5 mL/min/1.73 m2; median proteinuria 0.64 g/day), 43 (7.3%) reached the primary outcome during a median 78-month follow-up. Proteinuria at all time points was independently associated with kidney outcomes, with the 18-month measurement providing the best model fit. A threshold of 0.44 g/day (or g/gCr) yielded 79% sensitivity and 81% specificity, and patients with proteinuria ≥ 0.44 g/day at 18 months had significantly worse outcomes. Cox regression confirmed a robust association for 18-month proteinuria, irrespective of treatment type or timing. Conclusions: Proteinuria measured 18 months post-biopsy showed the strongest association with long-term kidney outcomes in IgAN, supporting its use as a universal treatment target across heterogeneous post-biopsy clinical courses.

Background: TAFRO syndrome (TAFRO) and POEMS syndrome (POEMS) are rare systemic inflammatory diseases with significant clinical, histological, and immunological overlaps with idiopathic multicentric Castleman disease (iMCD). While a high incidence of renal symptoms is observed in TAFRO and POEMS, the specific histopathological differences in their renal manifestations are not fully understood. Methods: This retrospective, multicenter study was conducted by the Japanese Renal Pathology Society (JRPS). Eighteen patients with TAFRO (n = 7), POEMS (n = 6), and iMCD (n = 5) were registered by members of the JRPS, and their clinicopathological findings were analyzed. Morphological examinations were performed using light, fluorescence, and electron microscopy. Immunohistochemical studies and semi-quantitative scoring systems have been used for detailed assessment of glomerular lesions. Results: Clinical data indicated that the time from disease onset to biopsy was significantly shorter in TAFRO patients than POEMS patients. Although immunosuppressive therapy induced improvement in all TAFRO patients, some POEMS patients exhibited a poor renal prognosis. Glomerular endothelial injury was observed in both the TAFRO and POEMS; however, the characteristics differed: the former displayed endotheliosis, whereas the latter exhibited membranoproliferative glomerulonephritis (MPGN)-pattern injury. Laminated short-linear structures of the subendothelial space were observed in both the TAFRO and POEMS using electron microscopy. Conclusions: Morphological characteristics of the process of renal glomerular damage and repair in TAFRO and POEMS were revealed. The differences in endotheliosis and MPGN-pattern injury in these diseases may reflect differences in the timing of renal biopsy and the clinical course.

Histopathology is a microscopic anatomical study of body tissues and widely used as a cancer diagnosing method. Generally, pathologists examine the structural deviation of cellular and sub-cellular components to diagnose the malignancy of body tissues. These judgments may often subjective to pathologists' skills and personal experiences. However, computational diagnosis tools may circumvent these limitations and improve the reliability of the diagnosis decisions. This paper proposes a prostate image classification method by extracting textural behavior using multifractal analysis. Fractal geometry is used to describe the complexity of self-similar structures as a non-integer exponent called fractal dimension. Natural complex structures (or images) are not self-similar, thus a single exponent (the fractal dimension) may not be adequate to describe the complexity of such structures. Multifractal analysis technique has been introduced to describe the complexity as a spectrum of fractal dimensions. Based on multifractal computation of digital imaging, we obtain two textural feature descriptors; i) local irregularity: alpha and ii) global regularity: f(alpha). We exploit these multifractal feature descriptors with a texton dictionary based classification model to discriminate cancer/non-cancer tissues of histopathology images of H&E stained prostate biopsy specimens. Moreover, we examine other three feature descriptors; Gabor filter bank, LM filter bank and Haralick features to benchmark the performance of the proposed method. Experiment results indicated that the performance of the proposed multifractal feature descriptor outperforms the other feature descriptors by achieving over 94% of correct classification accuracy.

The loss of insulin-producing pancreatic beta-cells in Type 1 diabetes mellitus (DM) is presumably the result of a T cell-mediated process. In general, CD8+ T cells are the predominant lymphocytes in the insulitis lesions, and CD4+ T cell-dominant insulitis is very rare. We present a case of a 72-year-old woman presented with excessive thirst and a 3-month history of weight loss. She was in a state of ketosis, and her plasma glucose concentration and HbA1c value were elevated. Moreover, anti-islet autoantibodies were positive, thus acute-onset Type 1 DM was diagnosed. At the time of diagnosis, a tumour was detected in the pancreas; total pancreatectomy was carried out 2 months later. The pathological diagnosis was intraductal papillary mucinous adenoma. Immunohistochemical staining of a sample of non-tumorous pancreatic tissue revealed 13 insulitis lesions infiltrated by both CD4+ and CD8+ T cells, and interestingly there were more CD4+ T cells than CD8+ T cells in the lesions. Moreover, B cells and macrophages had also infiltrated the lesions, and these two cell frequencies were both positively correlated with CD4+ as well as CD8+ T cell frequencies. This was a rare case with acute-onset Type 1 DM characterized by CD4+ T cell-dominant insulitis. Proinflammatory cytokines that can promote beta-cell apoptosis or CD8+ T cell function are reported to be secreted from CD4+ T cells. Thus, together with B cells and macrophages, CD4+ T cell-associated immune responses may have, directly and/or indirectly, played a role in the pathogenesis of the Type 1 DM in this patient.

© 2018, ISAROB. Advances in whole-slide scanning have led to research on digital pathology, including monitor-based diagnosis, feature quantification, and computer-aided diagnosis. The color variations due to the staining process and scanning device are a serious issue that should be solved in whole-slide imaging applications, and methods for color correction have been studied. Nevertheless, the effectiveness of color-correction methods in the quantitative analysis of histopathological images acquired by different whole-slide scanners (WSSs) has not been confirmed. In this work, several liver tissue samples were scanned by different WSSs, and a color-correction method for whole-slide images was applied to the digitized tissue specimens. A set of histological features were extracted from the histopathological images, both without and with color correction, to analyze the effectiveness of the color-correction method in feature quantification and cancer identification.

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1-2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1-2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

Key Points – Elevated fractional excretion of potassium (FEK) at biopsy predicts a lower rate of proteinuria remission in adults with nephrotic syndrome. FEK levels vary by histologic types, being low in minimal change disease and high in diabetic kidney disease, suggesting diagnostic utility. FEK shows a dose-dependent link with remission, supporting its use as a simple prognostic biomarker. Background – Reliable prognostic biomarkers of nephrotic syndrome (NS) are crucial for optimizing patient management. The fractional excretion of potassium (FEK) reflects net tubular potassium handling, but its association with prognosis in NS remains unexplored. We aimed to investigate the association between baseline FEK and proteinuria remission in adult NS.Methods – This multicenter retrospective cohort study was conducted across nine institutions in Japan. We enrolled adult patients diagnosed with NS who underwent a native kidney biopsy and had FEK between January 2012 and June 2022. Patients were categorized based on FEK levels and followed until the first complete remission of proteinuria.Results – A total of 401 patients (median age, 61 years; 43% female) were included. Study participants were stratified into two groups based on the FEK cutoff value of 10%. Patients with high FEK had a significantly lower cumulative incidence of complete remission compared with those with low FEK (P < 0.001, log-rank test). In multivariable Cox regression analysis, high FEK was independently associated with a lower likelihood of complete remission (hazard ratio, 0.53; 95% confidence interval, 0.36 to 0.78). The trend of this association was observed across most subgroups, including those based on histologic diagnosis of minimal change disease and non–minimal change disease. Further stratification into four FEK categories revealed a progressive decline in remission rates with increasing FEK, indicating a dose-dependent relationship.Conclusions – Elevated FEK is an independent predictor of a lower likelihood of proteinuria remission in Japanese adults with NS. FEK may serve as a readily accessible and valuable prognostic biomarker in the clinical management of NS.