Papers - Hashiguchi, Akinori

DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages

Nishimura E.S., Hishikawa A., Nakamichi R., Akashio R., Chikuma S., Hashiguchi A., Yoshimoto N., Hama E.Y., Maruki T., Itoh W., Yamaguchi S., Yoshino J., Itoh H., Hayashi K.

Nature Communications 16 ( 1 ) 3958 2025.12

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DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6C^hi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.

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Polyclonal immunoglobulin G deposits with distinctive appearance in the tubular basement membrane: a report of two cases

Sakamaki Y., Hashiguchi A., Konishi K., Araki T., Tokuyama H.

BMC Nephrology 26 ( 1 ) 591 2025.12

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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.

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Human chorionic gonadotropin-positive cystic duct carcinoma with trophoblastic differentiation that exhibited an aggressive clinical course.

Takemura Y, Matsuda K, Abe Y, Hashiguchi A, Kitago M, Nakano Y, Sonoda K, Kitagawa Y

BMJ case reports 18 ( 11 )  2025.11

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Quantification-based explainable artificial intelligence for deep learning decisions: clustering and visualization of quantitative morphometric features in hepatocellular carcinoma discrimination.

Takagi G, Takeyama S, Abe T, Hashiguchi A, Sakamoto M, Suzuki K, Yamaguchi M

Journal of medical imaging (Bellingham, Wash.) 12 ( 6 ) 061407 2025.11

Joint Work,  ISSN  2329-4302

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Association Between Urinary Fractional Excretion of Potassium and Proteinuria Remission in Adult Nephrotic Syndrome.

Yoshida R, Nakayama T, Mitsuno R, Komatsu M, Oshima Y, Iwabuchi S, Itoh T, Matsumoto D, Kusahana E, Hoshi K, Nakamura K, Fujii K, Hara Y, Kawaguchi T, Futatsugi K, Yamaji Y, Tokuyama H, Murakami M, Takimoto C, Matsuda H, Ando T, Hashiguchi A, Kaneko Y, Azegami T, Hayashi K

Kidney360  2025.10

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Phenotype-dependent heterogeneity of THSD7A expression in gastric cancer tissue in a patient with THSD7A-associated membranous nephropathy

Minezaki C., Azegami T., Hashiguchi A., Nakayama T., Yoshimoto N., Hishikawa A., Hagiwara A., Hayashi K.

Cen Case Reports 14 ( 5 ) 693 - 699 2025.10

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An 88-year-old Japanese man with benign prostatic hyperplasia was presented to our hospital because of proteinuria and generalized edema. He was diagnosed with nephrotic syndrome and underwent a kidney biopsy, which revealed thickening of the capillary wall, spike formation, and subepithelial deposits, leading to histopathological diagnosis of membranous nephropathy. IgG4-dominant deposits were observed in IgG subclass staining, and immunostaining for thrombospondin type 1 domain-containing 7A (THSD7A) demonstrated granular staining along the capillary wall. A malignancy screening was performed, which led to the detection of gastric cancer. Malignancy-associated membranous nephropathy secondary to gastric cancer was suspected, and priority was given to the treatment of gastric cancer. Three months after undergoing radical surgery for gastric cancer, his nephrotic syndrome achieved remission. The histopathological diagnosis of gastric cancer was papillary adenocarcinoma. In the surgical specimen of the gastric cancer, THSD7A was positive in the tumor cells with intestinal phenotype and negative in gastric foveolar phenotype. These findings suggest that the acquisition of the ability to express THSD7A by cancer transformation in multi-step carcinogenesis of gastric cancer may be involved in the development of malignancy-associated membranous nephropathy.

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Tubulointerstitial nephritis with predominant monotypic plasma cell infiltration in three cases of Sjögren's syndrome: case reports and literature review

Miyauchi H., Azegami T., Hashiguchi A., Misaki M., Kawaguchi T., Hanaoka H., Muramatsu M., Soga T., Ando T., Kubota E., Nakayama T., Yoshimoto N., Hishikawa A., Hagiwara A., Kaneko Y., Hayashi K.

Cen Case Reports 14 ( 5 ) 774 - 780 2025.10

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Tubulointerstitial nephritis (TIN) is a common kidney manifestation of Sjögren's syndrome, typically characterized by interstitial infiltration of T and B cells, with plasma cells being more prominent than in other etiologies. While most plasma cell infiltration in TIN is polytypic and the importance of the immunoglobulin isotypes expressed by the infiltrating plasma cells in the pathogenesis is unknown, recent reports have identified rare cases with monotypic IgA-positive plasma cell infiltration accompanied by monoclonal gammopathy of undetermined significance (MGUS). Here, we present three cases of Sjögren syndrome-associated TIN characterized by monotypic plasma cell infiltration. In all cases, the isotype of the infiltrating plasma cells was consistent with that of the predominant serum immunoglobulin. One patient exhibited IgA-type MGUS, one had IgM-type MGUS, and one showed elevated serum IgG levels along with IgG-positive plasma cell infiltration, but without detectable paraproteinemia. Notably, serum immunoglobulin levels decreased in parallel with improvement in kidney function. These findings suggest a potential link between the systemic immunoglobulin profile and local immunopathology of the kidneys in Sjögren's syndrome. Further case accumulation is needed to clarify the clinical significance and pathophysiology of monotypic plasma cell infiltration in TIN associated with Sjögren's syndrome.

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A case of IgA nephropathy associated with Crohn’s disease treated with enteric-coated budesonide

Yoshida R., Nakayama T., Hashiguchi A., Azegami T., Hayashi K.

Cen Case Reports 14 ( 4 ) 659 - 664 2025.08

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The gut–kidney axis has recently gained attention as a pathogenesis of IgA nephropathy (IgAN). In fact, the efficacy of target-release formulation of budesonide for IgAN has been reported in recent studies. On the other hand, there have been no reports yet on the efficacy of enteric-coated budesonide for IgAN complicated with inflammatory bowel disease. We report a case of IgAN with comorbid Crohn’s disease (CD) treated with a combination of enteric-coated budesonide and methylprednisolone pulse therapy. The patient was followed for 2 years. He showed initial reduction in proteinuria following treatment. However, after discontinuation of enteric-coated budesonide therapy, proteinuria recurred despite well-controlled CD. Enteric-coated budesonide combined with methylprednisolone pulse therapy may be effective in short-term reduction of proteinuria while minimizing systemic steroid side effects in IgAN associated with CD. However, the tendency for relapse suggests the need for long-term management strategies. Therefore, further research is needed to establish optimal treatment protocols for this patient population.

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An adolescent presenting with IgA nephropathy and persistent decreased kidney function after COVID-19 vaccination during follow-up for asymptomatic hematuria: a clinicopathological study

Morisawa K., Takahashi T., Matsuoka K., Hashiguchi A., Yamanaka M., Hamada R., Honda M.

Cen Case Reports 14 ( 4 ) 635 - 640 2025.08

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Although the coronavirus disease 2019 (COVID-19) vaccine has been proven to be effective and safe in most adults and children, various diseases, including IgA nephropathy, sometimes occur as an adverse effect. We herein describe a case of IgA nephropathy in a 16-year-old, male patient with persistent kidney dysfunction following COVID-19 vaccination and present the clinicopathological course of the disease. The patient presented to the outpatient clinic with a history of gross hematuria 6 days after receiving the COVID-19 vaccine. Prior to the current presentation, he was being examined regularly at an outpatient clinic for asymptomatic hematuria. His mother had received a diagnosis of IgA nephropathy, and his younger brother had received a diagnosis of asymptomatic hematuria. A blood test of this patient demonstrated elevated serum creatinine, and IgA nephropathy was pathologically diagnosed (Oxford classification M0E1S1T0C1). Prednisolone and immunosuppressants were administered promptly to treat the decreased kidney function and the pathology. Nevertheless, the failure of his kidney function to recover to the state it was in prior to this episode may have led to the formation of chronic lesions, causing irreversible kidney tissue damage. Some patients with IgA nephropathy, asymptomatic hematuria or a family history of kidney-related symptoms may experience kidney dysfunction after COVID-19 vaccination and require prednisolone or immunosuppressive therapy to stem the progressive deterioration of their kidney function. Prior to receiving the COVID-19 vaccine, patients with any of these conditions should be provided with an appropriate explanation of the risks and be asked for their consent to be vaccinated.

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Taurine supplementation improves physical activity level in a hemodialysis patient with mitochondrial disease: a case report

Yoshida R., Mitsuno R., Nakayama T., Azegami T., Hashiguchi A., Torimitsu T., Yoshimoto N., Hisikawa A., Hagiwara A., Nakamura T., Meguro S., Katsumata M., Endo J., Matsunaga T., Yoshino J., Kanda T., Morimoto K., Monkawa T., Yoshida T., Nakahara J., Yamaguchi S., Hayashi K.

Cen Case Reports 14 ( 3 ) 366 - 373 2025.06

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Mitochondrial diseases (MDs) are inherited metabolic disorders that affect multiple organ systems, including the kidneys. Variability in disease onset and phenotypic expression, combined with the absence of specific kidney pathological findings, pose significant challenges in diagnosing MD. Consequently, many undiagnosed cases of MD may exist among patients undergoing dialysis. No effective treatment for mitochondrial nephropathy has been established. We report the case of a 27-year-old female patient who presented with leg edema, nephrotic range proteinuria attributed to focal segmental glomerulosclerosis, and bilateral sensorineural hearing loss. Immunosuppressive therapy failed to achieve remission, resulting in progressive kidney function decline and eventual end-stage kidney disease. At hemodialysis initiation, worsening atypical cardiac function and hypertrophy prompted genetic testing, which identified an MT-TL1 m.3243 A > G mutation and confirmed the diagnosis of MD. After hemodialysis initiation, the patient experienced persistent fatigue and decreased physical activity levels despite dry weight management. Suspected stroke-like symptoms prompted the initiation of taurine supplementation, which significantly improved headache severity, cardiac function, and physical activity levels. This case highlights the therapeutic potential of taurine supplementation in patients with MD undergoing dialysis and the importance of maintaining clinical vigilance for MD across all stages of chronic kidney disease, even without characteristic renal pathological findings of mitochondrial nephropathy.

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Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis.

Kazuoto Hiramoto, Shuntaro Saito, Hironari Hanaoka, Jun Kikuchi, Hiroyuki Fukui, Akinori Hashiguchi, Katsuya Suzuki, Tsutomu Takeuchi, Yuko Kaneko

Arthritis & rheumatology (Hoboken, N.J.) 77 ( 3 ) 298 - 310 2025.03

Joint Work,  ISSN  23265191

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OBJECTIVE: There is a pressing need to understand the pathogenesis of histological findings and identify the biomarkers for predicting the histological severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histological findings in LN. METHODS: Urine samples from patients with biopsy-proven active LN were screened for 1305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histological features in LN were quantified to identify the urinary proteins associated with the histological findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localisation of the candidate proteins. RESULTS: Cluster analysis extracted five histological subgroups according to their correlations with each histological finding in LN. Protein groups which correlated with each histological subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), MCP-1, and IGFBP-5 levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localisation of these proteins in each lesion. CONCLUSIONS: Renal histological findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histological findings in LN.

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Urine-to-blood urea nitrogen ratio predicts proteinuria remission in nephrotic syndrome

Mitsuno R., Nakayama T., Yoshida R., Komatsu M., Oshima Y., Iwabuchi S., Hoshi K., Itoh T., Matsumoto D., Fujii K., Hara Y., Futatsugi K., Kawaguchi T., Ando T., Matsuda H., Yamaji Y., Murakami M., Yoshino J., Hashiguchi A., Kaneko Y., Azegami T., Hayashi K.

Clinical and Experimental Nephrology  2025

Joint Work,  ISSN  13421751

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Background: Nephrotic syndrome (NS) carries a high risk of severe complications and kidney failure, necessitating reliable prognostic markers. Given the link between tubular injury and poor remission of proteinuria, markers of tubular function may be informative in NS. The urine-to-blood urea nitrogen ratio (UBUR) reflects tubular urea handling, yet its prognostic value in NS is unclear. We evaluated whether baseline UBUR predicts proteinuria remission in adult NS. Methods: This multicenter retrospective study included patients with NS who underwent kidney biopsy between January 2012 and June 2022. Patients were followed from kidney biopsy until complete remission, dialysis initiation, death, or the end of the observation period (12 months after kidney biopsy). Results: A total of 237 patients (median age, 63 years; 47% female) were included, and divided into two groups based on a UBUR cutoff of 25.4 determined by the receiver operating characteristic curve. Patients with high UBUR had a significantly higher cumulative incidence of complete remission compared to those with low UBUR (P < 0.001, log-rank test). In multivariable Cox regression analysis, high UBUR independently predicted a greater likelihood of complete remission (hazard ratio 2.30 [95% confidence interval 1.47–3.61]). This association persisted in the subgroup analyses for podocytopathies, defined as minimal change disease and focal segmental glomerulosclerosis. Conclusions: High UBUR independently predicts proteinuria remission in adults with NS. UBUR could have potential as a simple, valuable biomarker to help guide the management of NS.

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A Case of Membranous Nephropathy Associated with Syphilis: Correlative Light and Electron Microscopy Revealing the Localization of Neuron-derived Neurotrophic Factor within Subepithelial Electron Dense Deposits.

Chisato Minezaki, Tatsuhiko Azegami, Akinori Hashiguchi, Ayumi Yoshifuji, Norifumi Yoshimoto, Aika Hagiwara, Akihito Hishikawa, Kaori Hayashi

Internal medicine (Tokyo, Japan) 64 ( 14 ) 2202 - 2207 2024.12

Joint Work,  ISSN  0918-2918

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A 50-year-old man presented to our hospital with a fever, edema, and a rash. The clinical diagnosis was renal dysfunction, nephrotic syndrome, and syphilis. The patient was treated with benzylpenicillin, and his symptoms improved. A renal biopsy revealed membranous nephropathy (MN). Recently, neuron-derived neurotrophic factor (NDNF) was reported to be an antigen corresponding to syphilis-associated MN. In the present patient, immunofluorescence staining and immunoelectron microscopy revealed granular NDNF-positive findings within subepithelial deposits, suggesting the presence of NDNF-IgG immune complexes. Although the mechanism by which NDNF serves as a target antigen remains unclear, NDNF was found to colocalize within subepithelial immune complexes in syphilis-associated MN.

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The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study.

Ryunosuke Mitsuno, Takashin Nakayama, Wataru Ito, Tomomi Maruki, Ran Nakamichi, Keika Adachi, Norifumi Yoshimoto, Akihito Hishikawa, Aika Hagiwara, Shintaro Yamaguchi, Toshiaki Monkawa, Jun Yoshino, Akinori Hashiguchi, Tatsuhiko Azegami, Kaori Hayashi

Renal failure 46 ( 2 ) 2423839 - 2423839 2024.12

Joint Work,  ISSN  0886-022X

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IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and leads to end-stage kidney disease. The proteinuria selectivity index (PSI) has been used to assess the prognosis in nephrotic syndrome, but its predictive value in patients with IgAN remains unclear. This single-center retrospective cohort study included patients who diagnosed with IgAN between March 2012 and March 2020. The PSI was calculated at the time of kidney biopsy. Patients were followed up from the time of kidney biopsy to kidney replacement therapy, death, transfer to another facility, or study completion. Ninety-four patients with a median age of 51 years were enrolled and divided according to the cutoff value of PSI determined by the receiver operating characteristic curve analysis into low-PSI (PSI <0.243, n = 39) and high-PSI groups (PSI ≥0.243, n = 55). The median follow-up duration was 70 months. Rates of remission of proteinuria and survival without a two-fold increase in serum creatinine were significantly better in the low-PSI group (both p < 0.01, log-rank test). Cox regression analysis showed that a low PSI was significantly associated with an increased likelihood of remission of proteinuria and hematuria (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.02-3.85 and HR 1.75; 95% CI 1.01-3.13, respectively), and a decreased risk of a two-fold increase in serum creatinine (HR 0.10; 95% CI 0.01-0.81). In conclusion, The PSI could have the potential to support the assessment of the prognosis of IgAN, in addition to established prognostic markers, by reflecting the overall glomerular permeability.

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Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome.

Takashin Nakayama, Tatsuhiko Azegami, Shintaro Yamaguchi, Keita Hirano, Motoaki Komatsu, Kentaro Fujii, Koji Futatsugi, Hidenori Urai, Takahisa Kawaguchi, Tomoaki Itoh, Norifumi Yoshimoto, Aika Hagiwara, Akihito Hishikawa, Hiroto Matsuda, Takashi Ando, Yasuyoshi Yamaji, Marohito Murakami, Akinori Hashiguchi, Yuko Kaneko, Takashi Yokoo, Kaori Hayashi

Scientific reports 14 ( 1 ) 23755 - 23755 2024.10

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Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09-0.19) for MCD, 0.33 (0.23-0.40) for FSGS, and 0.20 (0.14-0.30) for MN. FENa were 0.24 (0.09-0.68), 1.03 (0.50-2.14), and 0.78 (0.41-1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97-3.81] and HR 1.93 [95% CI 1.46-2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome.

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Primary breast lymphoma mimicking triple-negative breast cancer: a case report with clinical and pathological implications.

Toyoaki Sawano, Masahiro Wada, Akihiko Ozaki, Akinori Hashiguchi, Shinichi Hirooka, Tetsuya Tanimoto

Surgical case reports 10 ( 1 ) 234 - 234 2024.10

Joint Work,  ISSN  2198-7793

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BACKGROUND: Primary breast lymphoma (PBL) is a rare type of extranodal lymphoma, the diagnostic process for which presents significant challenges owing to an overlap in clinical and pathological features with those observed in triple-negative breast cancer (TNBC). However, the current literature reveals a paucity of information regarding the ramifications of potential diagnostic errors, particularly in the context of emergent therapeutic strategies for TNBC. Thus, we present a unique report of a case of PBL. CASE PRESENTATION: A 76-year-old female with no past medical or family history presented to the hospital with the chief complaint of a mass in the right breast. Two masses were palpated in the right breast: one 56 mm mass (No. 1) located at 10 o'clock, and a 21 mm large, elastic, hard mass (No. 2) at 4 o'clock. Needle biopsy was performed only on the larger 56 mm mass (No. 1). The results showed invasive carcinoma that was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. The preoperative diagnosis was right breast cancer (T3N0M0 Stage IIB) of the TNBC subtype. The patient refused the preoperative chemotherapy recommended by the treatment team; therefore, right breast mastectomy and sentinel lymph-node biopsy were performed instead. The histopathological diagnosis of the first mass was diffuse large B-cell lymphoma (DLBCL); that of the second mass (No. 2) was an invasive breast carcinoma of no special type. Postoperative treatment consisted of endocrine therapy (letrozole) for breast cancer, while the DLBCL was treated with chemotherapy and three courses of intrathecal chemotherapy. At the time of this report, the patient is still living, and neither tumor had recurred in the 2 years following surgery. CONCLUSIONS: On rare occasions, PBL can preoperatively mimic TNBC. While this case did not lead to serious consequences, because surgery was eventually selected as the first therapy, clinicians should be aware that the diagnosis of PBL is challenging using only a core-needle biopsy and can often be misdiagnosed as TNBC.

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False-positive Serum Antiglomerular Basement Membrane Antibody due to Bovine Serum Albumin-containing Surgical Adhesive: A Case Report.

Ryuto Yoshida, Tatsuhiko Azegami, Shintaro Yamaguchi, Aika Hagiwara, Akihito Hishikawa, Norifumi Yoshimoto, Akinori Hashiguchi, Kaori Hayashi

Kidney medicine 6 ( 10 ) 100880 - 100880 2024.10

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Antiglomerular basement membrane (GBM) disease has a poor prognosis. The rapid detection of serum anti-GBM antibody using an enzyme immunoassay, which has a high sensitivity and specificity, leads to an early diagnosis and improved prognosis. We report a case of acute kidney injury with false-positive anti-GBM antibody. A man in his early fifties underwent aortic arch replacement using bovine serum albumin (BSA)-containing surgical adhesion. After intravenous administration of vancomycin for a fever, he developed acute kidney injury without an abnormal urinalysis, and his anti-GBM antibody titer (fluorescence enzyme immunoassay [FEIA]) was 70.4 IU/mL. A kidney biopsy showed acute tubular injury and minor glomerular abnormalities without immunoglobulin G deposits, suggesting no evidence of anti-GBM glomerulonephritis. Consistent with the false-positive anti-GBM antibody test results, anti-GBM antibody determined using a chemiluminescent enzyme immunoassay was negative. A serum sample showed crossbinding to the FEIA plate from which the GBM antigen was removed. This finding indicated a nonspecific reaction to BSA, which contains a coating solution for the FEIA plate. This reaction was likely caused by anti-BSA antibody produced using BSA-containing surgical adhesion. Our findings suggest emerging challenges in diagnosing anti-GBM disease. Nephrologists must remain vigilant regarding false-positive anti-GBM antibody test results, particularly in cases evaluated with immunoassays that contain BSA.

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機能性表示食品「紅麹コレステヘルプ」およびNSAIDs服用中に発症した完全型Fanconi症候群を伴う急性腎障害の1例

星 健太, 村上 円人, 佐藤 芳紀, 杉浦 康平, 船木 裕規, 橋口 明典

日本腎臓学会誌 ((一社)日本腎臓学会)  66 ( 7 ) 1207 - 1214 2024.10

Joint Work,  ISSN  0385-2385

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薬剤性腎障害の原因は多岐にわたるが,漢方薬やサプリメントなど医薬品以外の物質の関与も多く,病歴を漏れなく聴取することが重要である。近年,機能性表示食品「紅麹コレステヘルプ」(小林製薬,大阪,日本)による健康被害の報告が多数のぼり,腎機能障害や尿所見異常などを呈し,一部の症例では末期腎不全に至るなどの臨床像が報告されているが,原因物質は未詳である。今回われわれは,以前より軽度の推算糸球体濾過量(estimated glomerular filtration rate:eGFR)低下を指摘されていたところへ同サプリメントを3年間内服継続し,発症2ヵ月前から非ステロイド性抗炎症薬(non-steroidal anti-inflammatory drugs:NSAIDs)を使用していたところに発症した急性腎障害(acute kidney injury:AKI),後天性完全型Fanconi症候群を伴った急性尿細管障害(acute tubular injury:ATI)の1例を経験した。初診時には尿中β2ミクログロブリン(β2 microglobulin:β2MG)および好中球ゼラチナーゼ結合リポカリン(neutrophil gelatinase-associated lipocalin:NGAL)の上昇と,汎アミノ酸尿,尿糖陽性,高カルシウム尿症,高リン尿症,高尿酸尿症,II型尿細管性アシドーシスといった近位尿細管機能異常を認め,Fanconi症候群を呈したATIによるAKIと考えられた。腎生検組織所見では尿細管上皮の傷害像はみられたが,炎症性細胞浸潤は乏しかった。足突起消失(foot process effacement)は部分的であった。ステロイドを含めた免疫抑制治療は行わず保存的治療のみで腎機能障害やFanconi症候群は軽快し,現在経過観察中である。全国的に使用されているサプリメントであり,原因物質の究明が待たれるが,同サプリメントにより惹起される腎機能障害や蛋白尿などの尿所見異常の病態を中心に,文献的考察を踏まえて報告する。(著者抄録)

Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

Tomoki Nagasaka, Kiyotaka Uchiyama, Eriko Yoshida Hama, Daiki Kojima, Kenji Kaneko, Norifumi Yoshimoto, Itaru Yasuda, Mamiko Yamada, Fuyuki Miya, Hisato Suzuki, Takaya Tajima, Shintaro Yamaguchi, Kaori Hayashi, Takeshi Kanda, Akinori Hashiguchi, Kenjiro Kosaki, Hiroshi Itoh

CEN case reports 14 ( 2 ) 208 - 216 2024.09

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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.

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Complement Receptor 1 Enhancement in Recurrent Membranous Nephropathy Following Kidney Transplantation: A Case Report.

Noriyuki Kounoue, Hideyo Oguchi, Akinori Hashiguchi, Kazuho Honda, Dedong Kang, Tetuo Mikami, Naobumi Tochigi, Takeshi Kawamura, Yoshihiro Itabashi, Takashi Yonekura, Kei Sakurabayashi, Ken Sakai

Kidney medicine 6 ( 9 ) 100876 - 100876 2024.09

Joint Work

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Membranous nephropathy (MN) recurs in some kidney allograft patients, and recurrence increases graft failure rates. We present a unique case of recurrent MN in first and second allografts showing glomerular capillary wall-positivity for complement receptor 1 (CR1) consistent with immunoglobulin G (IgG). A man in his late 20s developed MN and started hemodialysis. MN recurred and caused graft loss after the first transplantation and recurred again soon after the second transplantation. The IgG subclass staining was almost consistently negative for IgG4 and phospholipase A2 receptor (PLA2R)-staining was negative. Recurrent MN of unknown etiology was considered. Mass spectrometry demonstrated that CR1 had increased in the transplanted kidney biopsies. Immunohistochemistry and immunofluorescence studies demonstrated CR1 colocalized with IgG along glomerular capillaries in this case, whereas CR1 was localized in podocytes with no colocalization of IgG in a control case of PLA2R-associated MN. Correlative light and immunoelectron microscopy showed localization of CR1 at the interface between electron-dense deposits and podocytes. Collectively, this case demonstrated a unique enhancement and localization of CR1. MN with enhancement of CR1 has not been reported to date. CR1 may be a candidate causative antigen in this case of recurrent MN, although further study is needed to investigate the pathogenesis of CR1.

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