[RS3PE syndrome with angioimmunoblastic T-cell lymphoma early after the start of immunosuppressive therapy].

A 75-year-old man visited our Collagen Disease Department because of a fever, edema in the lower legs, and arthralgia. He presented with peripheral arthritis of the extremities and was negative for rheumatoid factor, leading to a diagnosis of RS3PE syndrome. A search for malignancy was performed, but no obvious malignant findings were found. After starting treatment with steroid, methotrexate, and tacrolimus, the patient's joint symptoms improved, but after five months, enlarged lymph nodes throughout the body were observed. A lymph node biopsy revealed a diagnosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders/angioimmunoblastic T-cell lymphoma (OI-LPD/AITL). After discontinuation of methotrexate and follow-up, no lymph node shrinkage was observed, and the patient had strong general malaise, so chemotherapy was started for AITL. After the start of chemotherapy, the patient's general symptoms improved quickly. RS3PE syndrome is a polyarticular, rheumatoid factor-negative, polyarticular synovitis with symmetric dorsolateral hand-palmar symmetric indentation edema that occurs mainly in elderly patients. It is also noted as a paraneoplastic syndrome, with 10%-40% of patients having malignant tumors. When our patient was diagnosed with RS3PE syndrome, a search for malignancy was performed, but there were no findings suggestive of malignant disease. However, after methotrexate and tacrolimus administration was started, the patient developed rapid lymph node enlargement, and the pathology showed AITL. The possibility of AITL as an underlying disease and RS3PE syndrome as a paraneoplastic syndrome, or conversely, OI-LPD/AITL associated with immunosuppressive therapy for RS3PE syndrome is considered. We herein report this case, as sufficient recognition is required for a proper diagnosis to be made and treatment of RS3PE syndrome to be performed.

Podocytes are lost from glomeruli before completing apoptosis.

Although apoptosis of podocytes has been widely reported in in vitro studies, it has been less frequently and less definitively documented in in vivo situations. To investigate this discrepancy, we analyzed the dying process of podocytes in vitro and in vivo using LMB2, a human (h)CD25-directed immunotoxin. LMB2 induced cell death within 2 days in 56.8 ± 13.6% of cultured podocytes expressing hCD25 in a caspase-3, Bak1, and Bax-dependent manner. LMB2 induced typical apoptotic features, including TUNEL staining and fragmented nuclei without lactate dehydrogenase leakage. In vivo, LMB2 effectively eliminated hCD25-expressing podocytes in NEP25 mice. Podocytes injured by LMB2 were occasionally stained for cleaved caspase-3 and cleaved lamin A but never for TUNEL. Urinary sediment contained TUNEL-positive podocytes. To examine the effect of glomerular filtration, we performed unilateral ureteral obstruction in NEP25 mice treated with LMB2 1 day before euthanasia. In the obstructed kidney, glomeruli contained significantly more cleaved lamin A-positive podocytes than those in the contralateral kidney (50.1 ± 5.4% vs. 29.3 ± 4.1%, P < 0.001). To further examine the dying process without glomerular filtration, we treated kidney organoids generated from nephron progenitor cells of NEP25 mice with LMB2. Podocytes showed TUNEL staining and nuclear fragmentation. These results indicate that on activation of apoptotic caspases, podocytes are detached and lost in the urine before nuclear fragmentation and that the physical force of glomerular filtration facilitates detachment. This phenomenon may be the reason why definitive apoptosis is not observed in podocytes in vivo.NEW & NOTEWORTHY This report clarifies why morphologically definitive apoptosis is not observed in podocytes in vivo. When caspase-3 is activated in podocytes, these cells are immediately detached from the glomerulus and lost in the urine before DNA fragmentation occurs. Detachment is facilitated by glomerular filtration. This phenomenon explains why podocytes in vivo rarely show TUNEL staining and never apoptotic bodies.

[Idiopathic esophageal submucosal hematoma during antithrombotic therapy for essential thrombocythemia].

A 73-year-old woman was hospitalized with sudden chest pain and hematemesis. Chest computed tomography and upper gastrointestinal endoscopy revealed an idiopathic submucosal hematoma from the cervical esophagus to the esophagogastric mucosal junction. Idiopathic esophageal submucosal hematoma is often prone to a bleeding tendency of an underlying disorder. The patient had a history of essential thrombocythemia (ET) and was taking aspirin. She successfully recovered after aspirin discontinuation and conservative treatment; however, died of cardiopulmonary arrest in the ward on day 9 of hospitalization. The autopsy revealed that the cause of death was pulmonary thromboembolism. This is the first report of ET with submucosal hematoma of the esophagus. The possibility of an esophageal submucosal hematoma should be considered when patients with ET complain of chest pain since ET and treatment with aspirin are considered risk factors for bleeding. Additionally, close attention should be focused on the risk of developing thrombosis if a patient with myeloproliferative neoplasm is required to discontinue antithrombotic therapy due to a bleeding event.

[Examination of the effect of immunosuppressive therapy on acquired hemophilia A in elderly patients with bloodstream infections].

AIM: Acquired hemophilia A (AHA) is an acquired autoantibody (inhibitor) against blood coagulation factor VIII (FVIII) that significantly reduces FVIII activity and causes a bleeding tendency. Immune acquired coagulation factor deficiency. The peak age of onset is in the 70s. In Japan, which has an aging society, the number of reports has recently been increasing, and it should be noted that AHA is a bleeding disease that can occur in the elderly. Examined 5 cases of AHA that were experienced in our hospital. The FVIII inhibitor level, APTT, underlying disease, treatment history, and outcome were retrospectively examined using medical records. RESULTS: The age of onset was 76-93 years. At the time of diagnosis, the Hb (mg/dL) value was 6.1-10.3, the APTT was 75.6-203.2 seconds, the FVIII inhibitor value (BU/mL) was 18-686, and the platelet count was within the normal range in all cases. Bleeding control was possible using a bypass hemostatic agent in 4 patients. All patients underwent immunosuppressive therapy. Two patients were discharged alive and 3 patients died. The cause of death was infectious disease in all cases. The total prednisolone-equivalent dose of the deceased patients was 1,240-3,206 mg; one patient was treated with cyclophosphamide and was treated with dexamethasone. CONCLUSION: Long-term immunosuppressive therapy is expected to increase the risk of infection in elderly patients. The risk assessment of AHA treatment-related bloodstream infections is insufficient, and it will be necessary to accumulate data and consider appropriate assessments and countermeasures.

Indirect podocyte injury manifested in a partial podocytectomy mouse model.

In progressive glomerular diseases, segmental podocyte injury often expands, leading to global glomerulosclerosis by unclear mechanisms. To study the expansion of podocyte injury, we established a new mosaic mouse model in which a fraction of podocytes express human (h)CD25 and can be injured by the immunotoxin LMB2. hCD25+ and hCD25- podocytes were designed to express tdTomato and enhanced green fluorescent protein (EGFP), respectively, which enabled cell sorting analysis of podocytes. After the injection of LMB2, mosaic mice developed proteinuria and glomerulosclerosis. Not only tdTomato+ podocytes but also EGFP+ podocytes were decreased in number and showed damage, as evidenced by a decrease in nephrin and an increase in desmin at both protein and RNA levels. Transcriptomics analysis found a decrease in the glucocorticoid-induced transcript 1 gene and an increase in the thrombospondin 4, heparin-binding EGF-like growth factor, and transforming growth factor-ß genes in EGFP+ podocytes; these genes may be candidate mediators of secondary podocyte damage. Pathway analysis suggested that focal adhesion, integrin-mediated cell adhesion, and focal adhesion-phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin signaling are involved in secondary podocyte injury. Finally, treatment of mosaic mice with angiotensin II receptor blocker markedly ameliorated secondary podocyte injury. This mosaic podocyte injury model has distinctly demonstrated that damaged podocytes cause secondary podocyte damage, which may be a promising therapeutic target in progressive kidney diseases.NEW & NOTEWORTHY This novel mosaic model has demonstrated that when a fraction of podocytes is injured, other podocytes are subjected to secondary injury. This spreading of injury may occur ubiquitously irrespective of the primary cause of podocyte injury, leading to end-stage renal failure. Understanding the molecular mechanism of secondary podocyte injury and its prevention is important for the treatment of progressive kidney diseases. This model will be a powerful tool for studying the indirect podocyte injury.

[Diffuse large B-cell lymphoma with mediastinal bulky mass associated with complication of repeated sinus arrest].

A 71-year-old woman presented to a clinic with the chief complaint of facial edema and dyspnea; chest radiography showed mediastinal mass shadow and right pleural effusion. Computed tomography guided biopsy of the mediastinal mass had been performed by her previous doctor, and she was diagnosed with diffuse large B-cell lymphoma. She was referred to our hospital for chemotherapy. Electrocardiography performed before initiating chemotherapy showed sinus arrest for about 4 s, and Holter electrocardiography showed sinus arrest for up to about 7.4 s, which was repeatedly observed 6 times, indicating sick sinus syndrome (SSS). The mediastinal mass completely excluded the superior vena cava, and considering the risk of infection, an extracorporeal pacemaker was not inserted. We believed that the tumor effect was the cause of sinus arrest; hence, chemotherapy initiation was prioritized. R-CHOP therapy preceding vincristine and prednisolone was started, and sinus arrest was not observed after initial treatment. SSS may have been caused by carotid hypersensitivity syndrome that involved the exclusion of carotid artery pressure receptors by the tumor or the direct stimulation of the vagus nerve by microtumor infiltration.

[Human herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma that developed during myelodysplastic syndrome].

Primary effusion lymphoma (PEL) is a large B-cell lymphoma that only proliferates proliferating effusion in the body cavity. It is associated with human herpesvirus 8 (HHV8).HHV8 negative effusion lymphoma, which is different from PEL in many ways, has also been reported and is referred to as HHV8-unrelated PEL-like lymphoma. This lymphoma is very rare and its clinical characteristics have not been fully clarified.A 79-year-old male developed HHV8-negative primary effusion lymphoma during treatment for myelodysplastic syndrome.Abdominal computed tomography revealed abdominal effusion, but did not show any evidence of a tumor mass or lymph node enlargement. A cytological analysis of his pleural effusion revealed atypical lymphoid cells that were negative for CD10, and positive for CD19 and CD20. Corticosteroids were administered to treat the abdominal effusion; however, the patient died of an exacerbation of lymphoma on the 20th day after the initiation of corticosteroid therapy. We herein report the case of an HIV seronegative elderly patient with HHV8-unrelated PEL-like lymphoma.

Risk Factors for Acute Kidney Injury and Chronic Kidney Disease following Allogeneic Hematopoietic Stem Cell Transplantation for Hematopoietic Malignancies.

BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

Global polysome analysis of normal and injured podocytes.

Podocyte injury is a key event for progressive renal failure. We have previously established a mouse model of inducible podocyte injury (NEP25) that progressively develops glomerulosclerosis after immunotoxin injection. We performed polysome analysis of intact and injured podocytes utilizing the NEP25 and RiboTag transgenic mice, in which a hemagglutinin tag is attached to ribosomal protein L22 selectively in podocytes. Podocyte-specific polysomes were successfully obtained by immunoprecipitation with an antihemagglutinin antibody from glomerular homogenate and analyzed using a microarray. Compared with glomerular cells, 353 genes were highly expressed and enriched in podocytes; these included important podocyte genes and also heretofore uncharacterized genes, such as Dach1 and Foxd2. Podocyte injury by immunotoxin induced many genes to be upregulated, including inflammation-related genes despite no infiltration of inflammatory cells in the glomeruli. MafF and Egr-1, which structurally have the potential to antagonize MafB and WT1, respectively, were rapidly and markedly increased in injured podocytes before MafB and WT1 were decreased. We demonstrated that Maff and Egr1 knockdown increased the MafB targets Nphs2 and Ptpro and the WT1 targets Ptpro, Nxph3, and Sulf1, respectively. This indicates that upregulated MafF and Egr-1 may promote deterioration of podocytes by antagonizing MafB and WT1. Our systematic microarray study of the heretofore undescribed behavior of podocyte genes may open new insights into the understanding of podocyte pathophysiology.

A case of infection-related glomerulonephritis with massive eosinophilic infiltration
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Infection-related glomerulonephritis (IRGN) is rarely complicated with eosinophil infiltration into the glomerulus. Here we report a case of eosinophilic proliferative glomerulonephritis related with infection. A 70-year-old man with respiratory symptoms displayed hypereosinophilia, hypocomplementemia, impaired renal function, and nephrotic syndrome. Renal biopsy revealed endocapillary proliferative glomerulonephritis with immunostaining for immunoglobulin G and complement 3, and subepithelial hump-like electron-dense deposits, thus fulfilling the criteria for IRGN. Immunostaining for the nephritis-associated plasmin receptor (NAPlr) in the glomerulus confirmed the diagnosis of IRGN. Of note, eosinophils infiltrated into the glomerular subendothelial spaces, renal tubules, peritubular capillaries, and the interstitium in the kidney as well as in the alveolar walls and pulmonary arteries in the lung. Corticosteroid therapy rapidly improved hypereosinophilia as well as respiratory symptoms and renal function. Urinary protein exertion was decreased, and serum level of complement and albumin was increased. These findings suggest that eosinophil infiltration might play a prominent role in respiratory and renal disorders. Severe endothelial damage of glomeruli and tubulointerstitial nephritis, caused by eosinophil-rich inflammation, might significantly contribute to exacerbation of renal insufficiency.
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JAK2 mutation and acute coronary syndrome complicated with stent thrombosis.

Acute coronary syndrome (ACS) could be a precious opportunity for patients to reveal concealed diseases other than conventional risk factors for ACS, such as hypertension, dyslipidemia, diabetes mellitus, etc. In the setting of ACS, the intracoronary and systemic prothrombotic environment has led to an increase in the risk of stent thrombosis of which mortality was higher among patients with ACS, especially with the highest mortality in patients with ST elevation myocardial infarction. The some specific conditions which were concealed beyond the cardiovascular pathophysiology except well-known risk factors for ACS and stent thrombosis might involve the onset of ACS. We describe a case of a 64-year-old man who was admitted to intensive care unit for chest pain. This case found the possibility that polycythemia vera with Janus kinase 2 (JAK2) V617F mutation might be a underlying disease of ACS with stent thrombosis, and highlighted the importance of recognizing polycythemia vera with JAK2 V617F mutation as concealed disease for cardiologists. We would like to report and review the relationship between ACS and polycythemia vera with JAK2 V617F mutation.

Unilateral ureteral obstruction attenuates intrarenal angiotensin II generation induced by podocyte injury.

The renal tissue renin-angiotensin system is activated in chronic kidney diseases. We previously demonstrated that intrarenal ANG II is synthesized primarily from liver-derived angiotensinogen filtered through the glomerulus and that podocyte injury increases the passage of angiotensinogen into the tubular lumen and generation of ANG II. In the present study, we tested the effect of cessation of glomerular filtration by ureteral obstruction on renal ANG II generation in kidneys with podocyte injury under two experimental conditions. Ureteral obstruction is known to activate the renin-angiotensin system in nonproteinuric kidneys. Transgenic mice expressing hCD25 in podocyte (NEP25) were injected with 1.25 or 10 ng/g body wt of LMB2, a hCD25-targeted immunotoxin, subjected to unilateral ureteral ligation on the following day, and euthanized 7 and 4 days later, respectively. In both experiments, compared with the kidney in untreated wild-type mice, renal angiotensinogen protein, as assessed by immunostaining and Western blot analysis, was increased in the contralateral unobstructed kidney. However, it was markedly decreased in the obstructed kidney. Whereas intrarenal ANG II content was increased in the contralateral kidney compared with the untreated kidney (248 ± 83 vs. 106 ± 21 and 298 ± 185 vs. 64.8 ± 20 fmol/g kidney, respectively), this increase was suppressed in the obstructed kidney (161 ± 75 and 113 ± 34 fmol/g kidney, respectively), a pattern opposite to what we expected in obstructed kidneys without podocyte injury. Thus, our study indicates that the major source of increased renal ANG II in podocyte injury is filtered angiotensinogen.

Early growth response 1 as a podocyte injury marker in human glomerular diseases.

Background: In human glomerular diseases, visualizing podocyte injury is desirable since podocytes do not regenerate and podocyte injury leads to podocyte loss. Herein, we investigated the utility of immunostaining for early growth response 1 (EGR1), which is expressed in injured podocytes from the early stages of injury in animal experiments, as a podocyte injury marker in human glomerular diseases. Methods: This study included 102 patients with biopsy-proven glomerular diseases between 2018 and 2021. The proportion of EGR1 expression in podocytes (%EGR1pod) was analyzed in relation to clinical and histopathological features, including glomerular and urinary podocyte-specific markers. Results: %EGR1pod correlated significantly with the urinary protein:creatinine ratio, urinary nephrin and podocin mRNA levels, and glomerular podocin staining (rho = 0.361, 0.514, 0.487 and -0.417, respectively; adjusted P = .002, <.001, <.001 and <.001, respectively). Additionally, %EGR1pod correlated with cellular/fibrocellular crescents (rho = 0.479, adjusted P <.001). %EGR1pod was high in patients with glomerulonephritis, such as immunoglobulin A nephropathy (IgAN), lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis, and in those with podocytopathies, such as membranous nephropathy and primary focal segmental glomerulosclerosis, while %EGR1pod was low in patients with minimal change disease. In a subgroup analysis of IgAN, %EGR1pod was higher in Oxford C1 patients than in C0 patients. However, unexpectedly, patients with higher %EGR1pod were more prone to attain proteinuria remission, suggesting that EGR1 in the context of IgAN reflects reversible early injury. Conclusions: Our findings indicate that EGR1 is a promising potential marker for identifying active early podocyte injury in human glomerular diseases.

A 20-year follow-up study of identical twin sisters with immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN) is characterized by diverse clinicopathological phenotypes. Herein we present a follow-up study of previously reported identical twin sisters with IgAN. The older sister exhibited more severe kidney histopathology and proteinuria and a lower birthweight than did her younger sister, and only the older sister experienced two childbirths. These raised concerns regarding her kidney outcomes. However, with timely multidisciplinary treatments, the older sister's kidney function remained preserved after 20 years of IgAN history. Our findings indicate the significant contribution of environmental/epigenetic factors to IgAN progression and the need for tailored medical care corresponding to life events.

Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

BACKGROUND: Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS: The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS: In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS: The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

Neural epidermal growth factor-like 1 protein (NELL1)-associated membranous nephropathy with heterogeneous underlying diseases: a case report.

Neural epidermal growth factor-like 1 protein (NELL1) is a target antigen of membranous nephropathy (MN). NELL1-associated MN (NELL1-MN) was originally described as a primary form but has subsequently been associated with other diseases, including malignancies, pre-exposure to certain drugs, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and rheumatoid arthritis (RA). We present a case of a 78-year-old woman with long-standing RA who developed persistent proteinuria and was diagnosed with MN. Evaluation of the underlying cause revealed chronic active HCV infection and past HBV infection. The underlying cause was less likely to be drug-related; however, there was no evidence of malignancy. The patient was diagnosed with HCV-associated MN. At 4 years after the diagnosis of MN, the patient died of breast cancer with multiple metastases. Subsequent immunohistological analysis revealed that she had NELL1-MN, and her breast cancer tissue stained positive for NELL1. Our case illustrates the difficulty in establishing the underlying cause of NELL1-MN, even after diagnosis. However, the incidence of malignancies, particularly breast and prostate cancers, is higher in NELL1-MN than in MN with other target antigens. Therefore, malignancies are considered a priority for investigation because of their frequency and prognosis among patients with NELL1-MN.

Histiocytic Glomerulopathy With Noncrystalline Inclusion Associated With IgG-Kappa Plasma Cell Dyscrasia.

The kidney pathology of monoclonal gammopathy of renal significance varies greatly. In this report, we present a woman in her 20s with nephrotic syndrome and monoclonal immunoglobulin G kappa (serum and urine) without diabetes. She had a family history of nephrotic syndrome as well as hematologic and connective tissue disorders. A kidney biopsy showed nodular glomerulosclerosis, with the glomerular capillary full of histiocytes, which were strongly positive for kappa, not lambda. Immunoelectron microscopy revealed that histiocytes had infiltrated the glomerular subendothelial space, and enlarged lysosomes of histiocytes contained kappa light chains, without apparent crystalline formation. Bone marrow examination was negative for malignancy; thus, we diagnosed this case as histiocytic glomerulopathy with noncrystalline inclusion associated with immunoglobulin G-kappa plasma cell dyscrasia. Hematologic treatment with bortezomib and daratumumab decreased her level of serum kappa chain and proteinuria. Two years after diagnosis, her kidney function remained normal, urinary protein level decreased to 1 g/d, and free light-chain ratio decreased to 3.1.