Modifying T cell phenotypes using TYK2 inhibitor and its implications for the treatment of systemic lupus erythematosus.

OBJECTIVES: The tuning effects of JAK/TYK2 inhibitors on the imbalance between T follicular helper (Tfh) and T regulatory (Treg) cells, related to systemic lupus erythematosus (SLE) pathogenesis, were investigated using human peripheral blood samples. METHODS: Peripheral blood mononuclear cells from untreated patients with SLE and healthy controls were analysed. Tfh1 cells were identified in nephritis tissue, and the effect of Tfh1 cells on B-cell differentiation was examined by coculturing naïve B cells with Tfh1 cells. RESULTS: Tfh1 cell numbers were increased in the peripheral blood of patients, and activated Treg cell counts were decreased relative to Tfh1 cell counts. This imbalance in the Tfh to Treg ratio was remarkably pronounced in cases of lupus nephritis, especially in types III and IV active nephritis. Immunohistochemistry revealed Tfh1 cell infiltration in lupus nephritis tissues. Co-culture of Tfh1 cells (isolated from healthy individuals) with naïve B cells elicited greater induction of T-bet+ B cells than controls. In JAK/TYK2-dependent STAT phosphorylation assays using memory CD4+ T cells, IL-12-induced STAT1/4 phosphorylation and Tfh1 cell differentiation were inhibited by both JAK and TYK2 inhibitors. However, phosphorylation of STAT5 by IL-2 and induction of Treg cell differentiation by IL-2+TGFß were inhibited by JAK inhibitors but not by TYK2 inhibitors, suggesting that TYK2 does not mediate the IL-2 signalling pathway. CONCLUSIONS: Tfh1 cells can induce T-bet+ B cell production and may contribute to SLE pathogenesis-associated processes. TYK2 inhibitor may fine-tune the immune imbalance by suppressing Tfh1 differentiation and maintaining Treg cell differentiation, thereby preserving IL-2 signalling, unlike other JAK inhibitors.

Sarcomatoid malignant pleural mesothelioma: a case of long-term recurrence-free survival following curative intent surgery alone.

BACKGROUND: Curative intent surgery may be indicated for some patients with resectable early stage malignant pleural mesothelioma (MPM). However, sarcomatoid MPM is a highly aggressive subtype for which curative intent surgery is generally not recommended. CASE PRESENTATION: We present the case of a 63-year-old man who presented with dyspnea and chest tightness. Computed tomography revealed pleural thickening and nodular lesions. A pleural biopsy confirmed lymphohistiocytoid MPM (cT1N0M0, stage IA), prompting surgical intervention. The patient underwent left extrapleural pneumonectomy (EPP), and the final diagnosis was sarcomatoid MPM (pT2N0M0, stage IB). Although post-operative chemotherapy was planned, the patient refused additional treatment, because of the introduction of home oxygen therapy, and has remained recurrence-free for 10 years after the surgery. CONCLUSIONS: This case presents a noteworthy instance of achieving long-term recurrence-free survival solely through curative intent surgery for sarcomatoid MPM. It highlights the potential efficacy of surgical intervention in managing this aggressive subtype, offering a glimmer of hope for improved outcomes. Further research is warranted to better define the role of surgery in the treatment of sarcomatoid MPM.

Outcomes and pathologic response of primary lung cancer treated with tyrosine kinase inhibitor/immune checkpoint inhibitor before salvage surgery.

PURPOSE: Advances in primary lung cancer drug therapy have extended patients' survival, including patients with stage IV disease. This study assessed the safety and effectiveness of salvage surgery following tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) therapy in primary lung cancer. METHODS: A retrospective chart review was conducted of 2050 primary lung cancer surgeries performed at our institution between 2012 and 2022. The study included patients who underwent salvage surgery for unresectable lesions that became resectable or localized residual lesions after treatment. We investigated patients' clinicopathological characteristics, therapeutic responses, and survival outcomes. RESULTS: We identified eight cases of salvage surgery after TKI treatment and eight cases after ICI treatment. Five patients experienced early recurrence after surgery; however, the long-term outcome in the post-TKI group was favorable, with a median overall survival (OS) of 66 (range: 28-80) months. Postoperative recurrence was confined to local lymph node recurrence in one patient in the post-ICI group. Despite the relatively short observation period, the long-term prognosis remained promising, with a median OS of 18.7 (range: 9.7-55.8) months. CONCLUSIONS: Salvage surgery after TKI or ICI treatment can be safely performed, and the OS may be favorable.

Peritumoral Fat Content Identified Using Iterative Decomposition of Water and Fat with Echo Asymmetry and Least-squares Estimation (IDEAL) Correlates with Breast Cancer Prognosis.

PURPOSE: Adipocytes around aggressive breast cancer (BC) are less lipid different from naive adipocytes (cancer-associated adipocytes, CAAs), and peritumoral edema caused by the release of cytokines from CAAs can conduce to decrease the peritumoral fat proportion. The purpose of this study was to correlate peritumoral fat content identified by using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with lymph node metastasis (LNM) and recurrence-free survival (RFS) in BC patients and to compare with T2-weighted (T2WI) and diffusion-weighted images (DWI) analyses. METHODS: This retrospective study consisted of 85 patients who were diagnosed with invasive carcinoma of breast and underwent breast MRI, including IDEAL before surgery. The scan time of fat fraction (FF) map imaging using IDEAL was 33s. Four regions of interest (ROIs), which are 5 mm from the tumor edge, and one ROI in the mammary fat of the healthy side were set on the FF map. Then average peritumoral FF values (TFF), average FF values on the healthy side (HFF), and peritumoral fat ratio (PTFR, which is defined as TFF/HFF) were calculated. Tumor apparent diffusion coefficient (ADC) values were measured on ADC map obtained by DWI. Peritumoral edema was classified into three grades based on the degree of signal intensity around the tumor on T2WI (T2 edema). RESULTS: The results of stepwise logistic regression analysis for four variables (TFF, PTFR, T2 edema, and ADC value) indicated that TFF and T2 edema were significant factors of LNM (p < 0.01). RFS was significantly associated with TFF (p = 0.016), and 47 of 49 (95.9%) patients with TFF more than 85.5% were alive without recurrence. CONCLUSION: Peritumoral fat content identified by using IDEAL is associated with LNM and RFS and may therefore be a useful prognostic biomarker for BC.

CD34-Positive Spindle Cell Tumor With CTNNB1 Mutation: An Unusual Spindle Cell Variant of Sinonasal Glomangiopericytoma.

Sinonasal glomangiopericytoma is an uncommon mesenchymal tumor with a perivascular myoid phenotype, which is categorized as a borderline/low-grade malignant soft tissue tumor by the current World Health Organization Classification of Head and Neck tumors. Here, we present the case of a 53-year-old woman with an unusual spindle cell morphology of sinonasal glomangiopericytoma arising in the nasal cavity, mimicking solitary fibrous tumor. Microscopically, the tumor showed a cellular proliferation of spindle cells in fascicles including a focal long sweeping arrangement or whorls, or with a storiform growth pattern, associated with hemangiopericytoma-like gaping blood vessels embedded in a fibrous stroma. This arrangement of the spindle cells faintly indicated a solitary fibrous tumor rather than sinonasal glomangiopericytoma. Immunohistochemically, the tumor was positively reactive to not only beta-catenin (in the nuclei) but also CD34, although signal transducers and activators of transcription 6 was negative. Mutational analysis using Sanger sequencing detected a CTNNB1 mutation. We finally diagnosed the tumor as a sinonasal glomangiopericytoma, showing an unusual spindle cell variant. Such unusual spindle cell morphology with CD34-immunoreactivity potentially leads to an incorrect diagnosis of solitary fibrous tumor because such prominent fascicles including long sweeping structures, reminiscent of desmoid-type fibromatosis, have scarcely been described in the literature. Hence, careful morphological scrutiny using appropriate diagnostic adjuncts is necessary for correct diagnosis.

A delayed diagnosis of fascioliasis: The importance of appropriate fecal diagnostic method.

Fascioliasis, a zoonotic helminthiasis, occurs sporadically in Japan. In this report, we describe a case of fascioliasis that was initially difficult to diagnose because the fecal examination method was negative for the Fasciola sp. eggs. A 64-year-old man living in Shimonoseki City, Japan, presented with fatigue and anorexia. Laboratory tests showed hepatic dysfunction and eosinophilia. Abdominal dynamic contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested intrahepatic biliary cysts. Thereafter, fever and night sweats persisted, and positron emission tomography and biopsy of the porta hepatis lymph node were performed on suspicion of malignancy. However, histopathological diagnosis found non-specific inflammation. As fascioliasis was suspected due to eosinophilia and the multiple hepatic masses, fecal egg examination was performed by an external private laboratory, which adopted the flotation method and reported the absence of parasite eggs. However, fecal examination was retried in our laboratory using the formalin-ether concentration method, and we detected Fasciola sp. eggs. This case suggests that misdiagnosis may occur depending on the fecal examination method; thus, it is necessary to choose a suitable method for certain parasite species.

A PEDIATRIC CASE OF DISSEMINATED BARTONELLA HENSELAE INFECTION ACCOMPANIED BY MULTIPLE INTRACRANIAL LESIONS.

We report a pediatric case of disseminated Bartonella henselae infection accompanied by multiple intracranial lesions. The patient developed multiple intracranial lesions despite treatment with azithromycin and gentamicin. After switching to rifampicin, the clinical symptoms of the patient improved. Given its good penetration into the central nervous system, rifampicin may be recommended for the treatment of B. henselae infection accompanied by intracranial lesions.

Differential expression of IFN-α, IL-12 and BAFF on renal immune cells and its relevance to disease activity and treatment responsiveness in patients with proliferative lupus nephritis.

OBJECTIVE: Since molecularly targeted therapies are emerging for treating lupus nephritis (LN), this study aimed to assess the immunohistochemical findings of the cytokines in renal tissue and their pathological and clinical relevance in LN. METHODS: Fifty patients with proliferative LN formed the case group; 5 with LN class II, IgA nephropathy and 10 with idiopathic haematuria were enrolled as controls. Immunohistochemical analysis for CD3, CD20, interferon (IFN)-α, interleukin (IL)-12/p40 and B-cell activating factor (BAFF) was performed by scoring the number of positive cells/area of the cortex. All immunohistochemical investigations were performed on formalin-fixed paraffin-embedded renal tissue. Proliferative LN cases were grouped by the dominant expression of IFN-α, IL-12/p40 and BAFF, and subsequently, clinicopathological features were compared. RESULTS: Clinical data of patients with proliferative LN included urine protein creatinine ratio, 2.2 g/gCre; anti-double-stranded DNA antibody, 200.9 IU/mL; total complement activity (CH50), 21.9 U/mL and SLE Disease Activity Index, 19.8 points. Proliferative LN cases, including class III (n=18) and IV (n=32), were classified into three subgroups according to the immunohistochemical score based on the dominancy of IFN-α (n=17), IL-12 (n=16) and BAFF group (n=17) proteins. Hypocomplementaemia and glomerular endocapillary hypercellularity were significantly increased in the IFN-α group, whereas chronic lesions were significantly higher in the IL-12 group (p<0.05). The IFN-α group had a poorer renal prognosis in treatment response after 52 weeks. CONCLUSIONS: The immunohistochemistry (IHC) of IFN-α, IL-12 and BAFF for proliferative LN enabled grouping. Especially, the IFN-α and IL-12 groups showed different clinicopathological features and renal prognoses. The results indicated the possibility of stratifying cases according to the IHC of target molecules, which might lead to precision medicine.

Immunoglobulin G deposition on proximal tubules and the tubular basement membrane in acute tubular injury complicated with focal segmental glomerulosclerosis (FSGS): A possible prediction tool for subclinical FSGS.

Immunofluorescent deposition of immunoglobulin G (IgG) in the tubular basement membrane (TBM) has been evaluated in the diagnosis of various diseases; however, few studies have investigated the immunofluorescence of acute tubular injury (ATI). Herein, we attempted to clarify IgG expression in the proximal tubular epithelium and TBM in ATI due to various causes. Patients with ATI with nephrotic-range proteinuria, including focal segmental glomerulosclerosis (FSGS, n = 18) and minimal change nephrotic syndrome (MCNS, n = 8), ATI with ischemia (n = 6), and drug-induced ATI (n = 7), were enrolled. ATI was evaluated by light microscopy. CD15 and IgG double staining and IgG subclass staining were performed to evaluate immunoglobulin deposition in the proximal tubular epithelium and TBM. IgG deposition was identified in the proximal tubules only in the FSGS group. Furthermore, IgG deposition in the TBM was observed in the FSGS group showing severe ATI. IgG3 was predominantly deposited by the IgG subclass study. Our results indicate that IgG deposition in the proximal tubular epithelium and TBM suggests the leaking of IgG from the glomerular filtration barrier and its reabsorption by proximal tubules, which may predict disruption of the glomerular size barrier, including subclinical FSGS. FSGS with ATI should be included as a differential diagnosis when IgG deposition in TBM is observed.

PDGFRB and NOTCH3 Mutations are Detectable in a Wider Range of Pericytic Tumors, Including Myopericytomas, Angioleiomyomas, Glomus Tumors, and Their Combined Tumors.

Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification. These pericytic tumors form a continuous morphologic spectrum, including those with combined morphology. However, to our knowledge, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatosis. To assess their potential role in classifying pericytic tumors, we investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2; 1/2), myofibromas (3/6; 0/6), angioleiomyomas (2/13; 3/13), and glomus tumors (5/9; 1/9). Point mutations were identified in 3 tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), 12 tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and 9 tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A, and G1494S mutations were classified as "deleterious/damaging" by ≥4 of 6 pathogenicity prediction tools in silico. Five-mutation-positive tumors, including 1 myopericytoma-angioleiomyoma, 2 myopericytomatoses-myofibroma, 1 myofibroma-myopericytoma and 1 angioleiomyoma-myopericytoma, were of combined morphology. Therefore, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.

A case of giant cell arteritis complicated by polymyalgia rheumatica with scalp necrosis and refractory jaw claudication.

Scalp necrosis is a rare complication of giant cell arteritis (GCA); however, it is a predictor of severe disease. In this case study, a patient presented with GCA complicated by polymyalgia rheumatica with scalp necrosis. An 86-year-old woman was admitted to the hospital for pulsating headache, scalp pain, jaw claudication, and generalised pain. Bilateral temporal arteries were found to be distended and pulseless, and scalp necrosis was observed in the parietal region. Simultaneous high-resolution contrast-enhanced magnetic resonance imaging (MRI) sequences of the head, shoulder, and hip showed staining around the bilateral shallow temporal arteries, shoulder, and hip joints, which was confirmed as GCA with polymyalgia rheumatica using other examination findings. After treatment with early induction remission therapy, scalp necrosis healed, but jaw claudication persisted. Six months after the start of treatment, scalp necrosis was cured to full hair growth. Despite remission induction therapy combined with tocilizumab, the patient had persistent jaw claudication for several months. At that time, a high-resolution contrast-enhanced MRI re-examination was useful in assessing disease activity. GCA with scalp necrosis may cause prolonged jaw claudication reflecting the progression of ischaemic lesions, whereas the disease activity can be accurately assessed by combining MRI studies.

TGF-ß3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.

Remission of Granulomatosis with Polyangiitis Only After Resection of a Pulmonary Nodule.

Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous lesions and is classified as ANCA-associated vasculitis (AAV). We herein report a case of GPA that was remitted by resection of a pulmonary lesion without immunosuppressive therapy. We detected activated neutrophils and neutrophil extracellular traps (NET) formation in resected lung tissue by immunofluorescence. Activated neutrophils and NETs might be involved in the pathophysiology of AAV and induce the vicious cycle of ANCAs and NETs. In cases of GPA with no other severe lesions, the reevaluation of the disease activity after diagnostic resection is crucial for considering the need for immunosuppressive therapy.

Catastrophic antiphospholipid syndrome with Epstein-Barr virus-associated hemophagocytosis: A clinicopathological conference.

Catastrophic antiphospholipid syndrome (CAPS) is a severe variant of antiphospholipid syndrome associated with multiorgan thrombosis in a short term. We present the case of a 14-year-old immunocompetent girl who developed renal, intestinal, and pulmonary infarction; thrombocytopenia; and hemolytic anemia within 1 week. She was diagnosed with thrombotic microangiopathy. Hence, plasma exchange and corticosteroid therapy were initiated, which improved thrombocytopenia. However, the patient's platelet count decreased. Her general condition gradually worsened with eventual death. An autopsy revealed multiple infarctions in the kidneys bilaterally, jejunum, ileum, and pulmonary parenchyma. Microthrombi were not detected. Massive hemophagocytosis was observed in the splenic pulp, lymph nodes, and bone marrow. Several Epstein-Barr viruses (EBVs)-encoded small ribonucleic acid (RNA)-positive lymphocytes were also found in the bone marrow. The presence of antibodies to both viral capsid antigen-immunoglobulin G and EBV nuclear antigen indicated past infection. Antiphospholipid antibody was positive after her death. The patient was finally diagnosed with CAPS and EBV-associated hemophagocytosis, possibly due to EBV reactivation. Establishing a clinical diagnosis of CAPS was relatively difficult because two different causes of thrombocytopenia, CAPS and hemophagocytosis, led to a difficulty in understanding this case's pathogenesis.

Eosinophilic granulomatosis with polyangiitis exhibits T cell activation and IgG4 immune response in the tissue; comparison with IgG4-related disease.

OBJECTIVE: To study the pathophysiological differences of EGPA and IgG4-related disease (RD) by clarifying their clinical, pathological and immunological features. METHODS: Clinical and pathological findings were compared in patients with EGPA and IgG4-RD. Peripheral blood mononuclear cells were used for comprehensive flow cytometric analysis. RESULTS: An elevation of the IgG4 level was found in all EGPA cases, with the accompanying pathological findings of lymphocytic infiltration and fibrosis observed in 30.8% patients, and the elevation of IgG4/IgG ratio in 61.5% patients. However, actual IgG4 levels, as well as the degree of the infiltration of IgG4-positive plasma cells, were still higher in patients with IgG4-RD than patients with EGPA. Examination by ACR/EULAR classification criteria showed only 13.6% of the EGPA patients met entry criteria, while all of them met the exclusion criteria. In regard to the immunophenotyping, EGPA patients had increases in activated CD4 and CD8 T cells compared with the healthy controls. However, no such similar changes occurred in IgG4-RD patients. On the other hand, both the EGPA and IgG4-RD patient groups had correlated increased plasmablasts and Tfh. These results indicate the presence of two axes: namely, the activation of T cells and that of B cells. Both axes are present in EGPA, but the T cell activation axis was not observed in IgG4-RD. CONCLUSIONS: The elevation of serum IgG4 as well as pathological IgG4 infiltration are not specific. Meanwhile, EGPA and IgG4-RD differ in immunological phenotypes, indicating the possible importance of the predominant activation of T cells in the development of vasculitis.

A case of simultaneous onset of highly active systemic lupus erythematosus and IgG4-related renal disease.

The patient was a 73-year-old woman who had hair loss, purpura, and numbness of the soles for past 1 year. Three months prior, she was diagnosed with interstitial lung disease (ILD) and was admitted to our department. She was diagnosed with systemic lupus erythematosus (SLE) based on positive antinuclear antibodies 1280× (speckled type), hair loss, low white blood cell count, positive anti-cardiolipin and anti-ds-DNA antibodies, and lupus retinopathy. In addition, the patient was also diagnosed with immunoglobulin G (IgG)4-related disease (IgG4RD) based on high serum IgG4 levels, ILD, urine occult blood, protein, and cast, and renal histological findings showed endocapillary proliferative glomerulonephritis, increased IgG4 positive plasma cells, and characteristic storiform fibrosis. High-dose glucocorticoid therapy, hydroxychloroquine, and belimumab were administered, which improved the SLE symptoms of lupus retinopathy and peripheral neuropathy, as well as the IgG4RD symptoms of ILD and urinary findings. Herein, we report a rare case of simultaneous onset of IgG4-related nephropathy with active glomerular lesions and SLE, in which renal histology, including fluorescent antibodies, was crucial for diagnosis.

Nephrotic syndrome with acute kidney injury due to focal segmental glomerulosclerosis following long-term treatment with minodronate.

Although bisphosphonates are well known to cause kidney disease, there are very few published cases of focal segmental glomerulosclerosis (FSGS) following treatment with minodronate. Here we report the case of an 86-year-old woman who developed acute kidney injury and nephrotic syndrome after receiving monthly oral minodronate for 24 months. Kidney biopsy revealed cellular variant FSGS. Treatment was initiated with the discontinuation of minodronate followed by intravenous methylprednisolone pulse and prednisolone at 35 mg/day. Subsequently, the patient's renal function gradually worsened, requiring initiation of hemodialysis. However, renal function and proteinuria improved markedly and hemodialysis was withdrawn 1 month after the initiation of steroid therapy. This is, to our knowledge, the first published case of FSGS induced by long-term use of minodronate, and also the first case of cellular variant FSGS induced by bisphosphonates although collapsing variant of FSGS is commonly caused by bisphosphonates. Our study indicates that patients on bisphosphonates should be closely monitored for proteinuria and renal impairment, regardless of the type of bisphosphonate.

Focal segmental glomerulosclerosis and concurrent glomerular microangiopathy after long-term imatinib administration.

A 79-year-old Japanese man was admitted to our hospital because of proteinuria and kidney dysfunction. He was diagnosed with chronic myeloid leukemia 13 years before and was treated with imatinib. Deep molecular response was achieved but he developed 1+ proteinuria in the first year, which gradually worsened thereafter. Imatinib was discontinued 12 years later but proteinuria and kidney dysfunction were progressive. Percutaneous kidney biopsy revealed mild mesangial hyper-cellularity and matrix increase, swelling of endothelial cells, and partial double contours of glomerular tufts. Subendothelial edema in the interlobular artery was also noted. Immunofluorescence was not remarkable. Electron microscopy revealed endothelial injury with severe sub-endothelial edema. Since imatinib had already been discontinued, conservative therapy with maximal dose of azilsartan was administered. A second biopsy was performed 1 year later because of further deterioration of kidney function, which revealed markedly increased global glomerulosclerosis and severe interstitial fibrosis and tubular atrophy. Segmental glomerulosclerosis with podocyte hyperplasia was also observed. Electron microscopy revealed glomerulosclerotic changes and partially attenuated endothelial injury. Two and a half years later, proteinuria reduced, progression of kidney dysfunction slowed, and he was independent on dialysis therapy. Molecular response of chronic myeloid leukemia was also maintained. The clinical course suggested that endothelial and podocyte injuries were induced by imatinib, and that the nephrotoxic effects lasted for a few years after discontinuation.