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Francisella tularensis causes pulmonary tularemia and death in humans when left untreated. Here, using a novel aerosol infection model, we show that acute pulmonary Francisella novicida infection not only causes pneumonia and liver damage, but also induces dystrophic cardiac calcinosis (DCC) in BALB/c mice. C57BL/6 mice also develop pneumonia and hepatic damage, but fail to develop DCC. Development of DCC in BALB/c mice is associated with significant induction of RANKL but not osteopontin in their organs. Depletion of lung macrophages prior to infection markedly reduces pericarditis and calcification in BALB/c mice but does not increase their susceptibility to infection. [ABSTRACT FROM AUTHOR]

The patient was a 59 year old Caucasian female who presented with flank pain and gross hematuria. She had similar symptoms approximately 3 months ago prior to presentation and has been on antibiotics for presumed pyelonephritis. The clinical course, differential diagnosis and pathological findings are discussed in detail. [ABSTRACT FROM AUTHOR]

Staphylococcus infection-associated glomerulonephritis (SAGN) and primary IgA nephropathy (IgAN) are separate disease entities requiring different treatment approaches. However, overlapping histologic features may cause a diagnostic dilemma. An exploratory proteomic study to identify potential distinguishing biomarkers was performed on formalin fixed paraffin embedded kidney biopsy tissue, using mass spectrometry (HPLC–MS/MS) (n = 27) and immunohistochemistry (IHC) (n = 64), on four main diagnostic groups—SAGN, primary IgAN, acute tubular necrosis (ATN) and normal kidney (baseline transplant biopsies). Spectral counts modeled as a negative binomial distribution were used for statistical comparisons and in silico pathway analysis. Analysis of variance techniques were used to compare groups and the ROC curve to evaluate classification algorithms. The glomerular proteomes of SAGN and IgAN showed remarkable similarities, except for significantly higher levels of monocyte/macrophage proteins in SAGN—mainly lysozyme and S100A9. This finding was confirmed by IHC. In contrast, the tubulointerstitial proteomes were markedly different in IgAN and SAGN, with a lower abundance of metabolic pathway proteins and a higher abundance of extracellular matrix proteins in SAGN. The stress protein transglutaminase-2 (TGM2) was also significantly higher in SAGN. IHC of differentially-expressed glomerular and tubulointerstitial proteins can be used to help discriminate between SAGN and IgAN in ambiguous cases. [ABSTRACT FROM AUTHOR]

Background: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) is a disease entity classified under the group of "Monoclonal gammopathy-related kidney diseases", and can recur after transplant. Clinical remission of proteinuria in patients with PGNMIGD has been previously shown following anti-B cell and/or anti-plasma cell therapies. Our case is the first to show complete histologic resolution of the glomerular monoclonal IgG kappa deposits in a case of recurrent PGNMIGD in renal allograft after rituximab and steroid treatment. This is a novel finding and it shows that the deposits are amenable to therapy. This case also highlights the importance of IgG subclass staining in the recognition of the monoclonal nature of the deposits. It is particularly important in PGNMIGD because only 20 to 30% of patients with this disease are reported to have detectable monoclonal gammopathy, and the deposits do not have any organized substructure on electron microscopic examination. Morphologically, they resemble polyclonal immune-type deposits seen in other immune complex glomerulonephritides such as lupus nephritis, infection-associated glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN type I).Case Presentation: The patient is a 44 year old Caucasian male who received a living unrelated donor kidney transplant for end-stage renal disease diagnosed 7 years before transplant. The reported native kidney biopsy diagnosis was membranoproliferative glomerulonephritis (MPGN) with IgG, C3 and kappa restricted deposits. Fourteen months post-transplant, he presented with abrupt worsening of graft function, proteinuria and serum IgG kappa monoclonal spike. Allograft biopsy was consistent with recurrent PGNMIGD, considering the native kidney diagnosis and interval post-transplant. He underwent plasmapheresis, IV pooled immune globulin, steroid pulse and taper, and anti-CD-20 Rituximab therapy. Patient had gradual decline in proteinuria and complete resolution of the immune deposits on repeat biopsy 3 months later. Unfortunately he subsequently developed chronic antibody-mediated rejection and transplant glomerulopathy and graft failure 34 months post-transplant.Conclusions: In a transplant setting, repeat allograft biopsies are frequently performed for graft dysfunction. This provides a good opportunity to study the evolution of the immune deposits following treatment. Our case shows complete histologic resolution of the deposits in allograft PGNMIGD. [ABSTRACT FROM AUTHOR]

* Context.--Infection-related glomerulonephritis (IRGN) usually manifests as a proliferative immune-complex glomerulonephritis. The degree of renal dysfunction at presentation can vary. Association with histologic features on kidney biopsy remains unknown. Objective.--To study the correlation between renal function in IRGN at the time of biopsy and the severity of histologic features. Design.--Culture-proven IRGN cases at our facility were included and divided based on estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m². Patients' demographic and pathologic findings were obtained from electronic medical records and kidney biopsy reports. Results.--In total, 104 cases were diagnosed with IRGN on biopsy (mean age, 55.6 ± 15.6 years; male, n = 79 [76%]; median eGFR, 14.5 mL/min/1.73 m²), and 51 of 104 showed eGFR <15 mL/min/1.73 m². Among all the histologic features assessed, only percent tubules with red blood cell (RBC) casts showed statistical difference, being significantly higher in the lower-eGFR group (P = .004). Multivariable logistic regression analysis also showed that %tubules with RBC casts were associated with lower eGFR (odds ratio, 1.12; 95% CI, 1.01-1.24; P = .01). Patients with 5% or more RBC casts (n = 31) showed a lower eGFR (P = .02) and a higher %cellular crescent (P < .001) compared with those with less than 5% RBC casts. Patients with concomitant anticoagulant therapy (n = 11) showed higher percentages of RBC casts than those without anticoagulants (P = .02). Conclusions.--Particular attention to the extent of RBC casts on kidney biopsy is recommended in patients with IRGN because these portend worse renal dysfunction, more so in patients requiring anticoagulation (including for hemodialysis) because they are especially vulnerable to developing anticoagulant-related nephropathy. [ABSTRACT FROM AUTHOR]

Introduction: Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post‐transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. Methods: We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011‐2020). Additionally, delayed graft function (DGF) (n = 237), and no DGF (control, n = 1314) groups were included for survival analysis. Results: Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full‐blown TMA on consecutive biopsies. The overall and death‐censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P =.005 and.04, respectively). Conclusions: Isolated arterial mucoid intimal thickening in early post‐transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor‐derived arterial injury are important. [ABSTRACT FROM AUTHOR]

Protease‐activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR‐1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant‐related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR‐1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR‐1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR‐1 agonist TFLLR‐NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR‐1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR‐1 modulators in a dose‐depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran‐induced increase in the systolic blood pressure was not affected by PAR‐1 modulators. In conclusion, the normal function of PAR‐1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR‐1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury. [ABSTRACT FROM AUTHOR]

A 60-year-old woman with a past medical history of asthma presented with fulminant myocarditis 9 days after testing positive for SARS-CoV-2 and 16 days after developing symptoms consistent with COVID-19. Her hospital course was complicated by the need for veno-arterial extracorporeal membrane oxygenation, ventricular arrhythmias, and pseudomonas bacteremia. She ultimately recovered and was discharged to home with normal left ventricular systolic function. Thereafter, she developed symptomatic ventricular tachycardia, for which she received an implantable cardioverter-defibrillator and antiarrhythmic drug therapy. [ABSTRACT FROM AUTHOR]

Context.--Calcium oxalate (CaOx) deposits in a kidney biopsy specimen can be seen in acute or chronic kidney injury and in oxalate nephropathy. Although no established cutoff criteria to diagnose oxalate nephropathy versus incidental CaOx deposition in the kidney exist, these conditions require different treatment. We noticed a significant decrease in the number of CaOx deposits in the kidney biopsy cores that were fixed in Michel transport medium (MTM) as compared to their counterparts fixed in formalin. Objective.--To investigate the impact of different fixatives on the number of CaOx deposits in kidney biopsy specimens. Design.--Retrospective search for kidney biopsies with diagnosis of CaOx deposition was performed in our Renal Pathology Database between January 1, 2015 and October 15, 2018. Results.--Seventy-six biopsies with an increased number of CaOx deposits were identified. CaOx deposits were counted on slides from the frozen tissue (MTM fixed or fresh frozen) and from the formalin-fixed cores. The density of CaOx deposits was significantly higher in formalin-fixed cores (13.6 ± 10.0/cm) than in MTM-fixed cores (3.2 ± 5.1/cm; P < .001). CaOx density in the kidney biopsy specimens decreased progressively with increased fixation time in MTM. No significant differences in the CaOx density between formalin-fixed and fresh frozen tissue were observed. Conclusions.--Our data demonstrate that fixation in MTM may result in a significant reduction in the number of CaOx deposits in a kidney biopsy specimen. This may make the diagnosis difficult, especially in small biopsy specimens with limited tissue in the formalin-fixed paraffin block. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes a simple, highly efficient and robust proteomic workflow for routine liquid-chromatography tandem mass spectrometry analysis of Laser Microdissection Pressure Catapulting (LMPC) isolates. Highly efficient protein recovery was achieved by optimization of a “one-pot” protein extraction and digestion allowing for reproducible proteomic analysis on as few as 500 LMPC isolated cells. The method was combined with label-free spectral count quantitation to characterize proteomic differences from 3000–10,000 LMPC isolated cells. Significance analysis of spectral count data was accomplished using the edgeR tag-count R package combined with hierarchical cluster analysis. To illustrate the capability of this robust workflow, two examples are presented: 1) analysis of keratinocytes from human punch biopsies of normal skin and a chronic diabetic wound and 2) comparison of glomeruli from needle biopsies of patients with kidney disease. Differentially expressed proteins were validated by use of immunohistochemistry. These examples illustrate that tissue proteomics carried out on limited clinical material can obtain informative proteomic signatures for disease pathogenesis and demonstrate the suitability of this approach for biomarker discovery. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article featuring the necessity of therapeutics in identifying protein distribution in renal amyloid deposits.

The article describes the case of a 34-year-old man who was hospitalized with a 6-month history of four, well-defined, non-tender, erythematous plaques on his right hand caused by Leishmania tropica. The patient has contracted an HIV infection from sex workers across India while working as a truck driver. Among the drugs taken by the patient were zidovudine, lamivudine, and nevirapine. It is noted that radiofrequency heat therapy was effective as a first-line treatment for cutaneous leishmaniasis.

Proteins are filtered from the blood through the glomerular filtration barrier. Filtered proteins are reabsorbed by proximal tubular epithelial cells (PTECs), which have been shown to possess the ability to regulate protein reabsorption. Histologically, these reabsorbed proteins are seen as tubular protein reabsorption droplets (TPRDs). Experimental studies indicate that PTECs play an important role in regulating proteinuria but the correlations between TPRD and the degree of proteinuria in human kidney biopsies have not been investigated in detail. Consecutive native kidney biopsies with non-proliferative glomerular disease performed at the OSUWMC for a 1-year period were analyzed. Cases with acute glomerular diseases and inadequate biopsies were excluded. The staining intensity and the percentage of TPRDs, as well as other morphologic parameters, were assessed. A total of 109 kidney biopsies were included in the study. A reverse correlation was identified between the percentage of albumin TPRDs and proteinuria ( p = 0.047). There were positive correlations between proteinuria and the staining intensity for IgG TPRDs ( p = 0.05) and the degree of acute tubular necrosis (ATN) ( p = 0.015). In patients with no ATN, positive correlations between proteinuria and albumin and IgG TPRDs were seen, whereas in patients with ATN, these correlations were lost. A positive correlation was seen between proteinuria and chronic kidney injury. A strong correlation was noted between the degree of proteinuria and podocyte foot process effacement. Our data indicate that PTECs regulate proteinuria by absorbing proteins from the urine filtrate. Therefore, based on the human renal biopsy material, our study confirms that well-functioning renal PTECs play an important role in the regulation of proteinuria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chow, Yildiz, Biederman, Dasgupta, Satoskar, Chow, Nadasdy and Brodsky.)

Anticoagulant related nephropathy (ARN) is the result of glomerular hemorrhage in patients on systemic anticoagulation therapy or underlying coagulopathy. Red blood cells (RBC) that passed through the glomerular filtration barrier form RBC casts in the tubules, increase oxidative stress and result in acute tubular necrosis (ATN). The mechanisms of ARN still not completely discovered. Plasminogen activator inhibitor-1 (PAI-1) plays a significant role in the maintenance of coagulation homeostasis. We developed an animal model to study ARN in 5/6 nephrectomy (5/6NE) rats. The aim of this study was to elucidate the role of PAI-1 in the ARN pathogenesis. 5/6NE rats were treated per os with warfarin (0.75 mg/kg/day) or dabigatran (150 mg/kg/day) alone or in combination with PAI-1 antagonist TM5441 (2.5, 5.0 and 10 mg/kg/day). TM5441 in a dose dependent manner ameliorated anticoagulant-induced increase in serum creatinine in 5/6NE rats. Anticoagulant-associated increase in hematuria was no affected by TM5441. The levels of reactive oxygen species (ROS) in the kidneys were in a dose-dependent manner decreased in 5/6NE rats treated with an anticoagulant and TM5441. Our data demonstrates that PAI-1 may reduce ARN by decreasing ROS in the kidneys. Glomerular hemorrhage is not affected by anti-PAI-1 treatment. These findings indicate that while symptoms of ARN can be reduced by PAI-1 inhibition, the main pathogenesis of ARN - glomerular hemorrhage - cannot be prevented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Medipally, Xiao, Biederman, Dasgupta, Satoskar, Parikh, Ivanov, Mikhalina and Brodsky.)

Background: Glomerulopathy with fibrillary deposits is not uncommon in routine nephropathology practice, with amyloidosis and fibrillary glomerulonephritis being the two most frequently encountered entities. Renal amyloid heavy and light chain (AHL) is relatively uncommon and its biopsy diagnosis is usually limited to cases that show strong equivalent staining for a single immunoglobulin (Ig) heavy chain and a single light chain, further supported by mass spectrometry (MS) and serum studies for monoclonal protein. But polyclonal light chain staining can pose a challenge., Case Summary: Herein we present a challenging case of renal AHL with polyclonal and polytypic Ig gamma (IgG) staining pattern by immunofluorescence. The patient is a 62-year-old Caucasian male who presented to an outside institution with a serum creatinine of up to 8.1 mg/dL and nephrotic range proteinuria. Despite the finding of a polyclonal and polytypic staining pattern on immunofluorescence, ultrastructural study of the renal biopsy demonstrated the presence of fibrils with a mean diameter of 10 nm. Congo red was positive while DNAJB9 was negative. MS suggested a diagnosis of amyloid AHL type with IgG and lambda, but kappa light chains were also present supporting the immunofluorescence staining results. Serum immunofixation studies demonstrated IgG lambda monoclonal spike. The patient was started on chemotherapy. The chronic renal injury however was quite advanced and he ended up needing dialysis shortly after., Conclusion: Tissue diagnosis of AHL amyloid can be tricky. Thorough confirmation using other available diagnostic techniques is recommended in such cases., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Context: Infection-related glomerulonephritis (IRGN) usually manifests as a proliferative immune-complex glomerulonephritis. The degree of renal dysfunction at presentation can vary. Association with histologic features on kidney biopsy remains unknown., Objective: To study the correlation between renal function in IRGN at the time of biopsy and the severity of histologic features., Design: Culture-proven IRGN cases at our facility were included and divided based on estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m2. Patients' demographic and pathologic findings were obtained from electronic medical records and kidney biopsy reports., Results: In total, 104 cases were diagnosed with IRGN on biopsy (mean age, 55.6 ± 15.6 years; male, n = 79 [76%]; median eGFR, 14.5 mL/min/1.73 m2), and 51 of 104 showed eGFR <15 mL/min/1.73 m2. Among all the histologic features assessed, only percent tubules with red blood cell (RBC) casts showed statistical difference, being significantly higher in the lower-eGFR group (P = .004). Multivariable logistic regression analysis also showed that %tubules with RBC casts were associated with lower eGFR (odds ratio, 1.12; 95% CI, 1.01-1.24; P = .01). Patients with 5% or more RBC casts (n = 31) showed a lower eGFR (P = .02) and a higher %cellular crescent (P < .001) compared with those with less than 5% RBC casts. Patients with concomitant anticoagulant therapy (n = 11) showed higher percentages of RBC casts than those without anticoagulants (P = .02)., Conclusions: Particular attention to the extent of RBC casts on kidney biopsy is recommended in patients with IRGN because these portend worse renal dysfunction, more so in patients requiring anticoagulation (including for hemodialysis) because they are especially vulnerable to developing anticoagulant-related nephropathy., (© 2024 College of American Pathologists.)

Background: Adoptive cellular therapy (ACT) with antibody-suppressor CXCR5 + CD8 + T cells (CD8 + T Ab-supp ) inhibits alloantibody production, antibody-mediated rejection (AMR), and prolongs graft survival in multiple transplant mouse models. However, it is not known how conventional immunosuppressive agents impact the efficacy of CD8 + T Ab-supp ACT., Methods: We investigated the efficacy of CD8 + T Ab-supp cell ACT when combined with calcineurin inhibitor (CNi) or mammalian target of rapamycin inhibitor (mTORi) in a murine model of kidney transplant., Results: ACT-mediated decrease in germinal center B cells, posttransplant alloantibody titer, and amelioration of AMR in high alloantibody-producing CCR5 knockout kidney transplant recipients were impaired when ACT was combined with CNi and enhanced when combined with mTORi. CNi (but not mTORi) reduced ACT-mediated in vivo cytotoxicity of IgG + B cells and was associated with increased quantity of germinal center B cells. Neither CNi nor mTORi treatment impacted the expression of cytotoxic effector molecules (FasL, Lamp1, perforin, granzyme B) by CD8 + T Ab-supp after ACT. Concurrent treatment with CNi (but not mTORi) reduced in vivo proliferation of CD8 + T Ab-supp after ACT. The increase in quantity of splenic CD44 + CXCR5 + CD8 + T cells that occurs after ACT was reduced by concurrent treatment with CNi but not by concurrent treatment with mTORi (dose-dependent)., Conclusions: Impaired efficacy of ACT by CNi is attributed to reduced persistence and/or expansion of CD8 + T Ab-supp cells after ACT. In contrast, concurrent immunosuppression with mTORi preserves CD8 + T Ab-supp cells quantity, in vivo proliferation, and in vivo cytotoxic effector function after ACT and enhances suppression of humoral alloimmunity and AMR., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although Staphylococcus aureus is the leading cause of acute infective endocarditis (IE) in adults, Bartonella spp. has concomitantly emerged as the leading cause of "blood culture-negative IE" (BCNE). Pre-disposing factors, clinical presentation and kidney biopsy findings in Bartonella IE-associated glomerulonephritis (GN) show subtle differences and some unique features relative to other bacterial infection-related GNs. We highlight these features along with key diagnostic clues and management approach in Bartonella IE-associated GN., Methods: We conducted a pooled analysis of 89 cases of Bartonella IE-associated GN (54 published case reports and case series; 18 published conference abstracts identified using an English literature search of several commonly used literature search modalities); and four unpublished cases from our institution., Results: Bartonella henselae and Bartonella quintana are the most commonly implicated species causing IE in humans. Subacute presentation, affecting damaged native and/or prosthetic heart valves, high titer anti-neutrophil cytoplasmic antibodies (ANCA), mainly proteinase-3 (PR-3) specificity, fastidious nature and lack of positive blood cultures of these Gram-negative bacilli, a higher frequency of focal glomerular crescents compared to other bacterial infection-related GNs are some of the salient features of Bartonella IE-associated GN. C3-dominant, but frequent C1q and IgM immunofluorescence staining is seen on biopsy. A "full-house" immunofluorescence staining pattern is also described but can be seen in IE -associated GN due to other bacteria as well. Non-specific generalized symptoms, cytopenia, heart failure and other organ damage due to embolic phenomena are the highlights on clinical presentation needing a multi-disciplinary approach for management. Awareness of the updated modified Duke criteria for IE, a high index of suspicion for underlying infection despite negative microbiologic cultures, history of exposure to animals, particularly infected cats, and use of send-out serologic tests for Bartonella spp. early in the course of management can help in early diagnosis and initiation of appropriate treatment., Conclusion: Diagnosis of IE-associated GN can be challenging particularly with BCNE. The number of Bartonella IE-associated GN cases in a single institution tends to be less than IE due to gram positive cocci, however Bartonella is currently the leading cause of BCNE. We provide a much-needed discussion on this topic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kitamura, Dasgupta, Henricks, Parikh, Nadasdy, Clark, Bazan and Satoskar.)

Amyloidosis is an infiltrative disease caused by misfolded proteins depositing in tissues. Amyloid infiltrates the kidney in several patterns. There are, as currently described by the International Society of Amyloidosis, 14 types of amyloid that can involve the kidney, and these types may have different locations or clinical settings. Herein we report a case of AA amyloidosis occurring in a 24-year-old male with a history of intravenous drug abuse and provide a comprehensive review of different types of amyloids involving the kidney., Competing Interests: The authors have no conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein, is essential for oligodendrocyte maturation and myelination; however, its role in the kidneys or in SOX9 regulation remains unknown. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: We have previously demonstrated that excessive anticoagulation with warfarin or dabigatran may result in acute kidney injury with red blood cell (RBC) tubular casts in some patients with chronic kidney disease, and this condition was named anticoagulant-related nephropathy (ARN). 5/6 nephrectomy (5/6NE) rats treated with warfarin or dabigatran reproduce the main pathologic features of human ARN. We had reported that 5/6NE C57BL/6 mice only partially develop ARN with increased serum creatinine and hematuria but no RBC tubular casts in the kidney., Objectives: The aim of this study was to investigate whether ARN can develop in 5/6NE 129S1/SvImJ mice., Methods: 5/6NE was performed in 129S1/SvImJ mice. Three weeks after 5/6NE, mice were treated with warfarin (1.0 and 1.5 mg/kg/day) or vehicle for 7 days. Serum creatinine, hematuria, and prothrombin time (PT) were monitored daily. Renal morphology was evaluated at the end of the studies., Results: Treatment with warfarin resulted in PT elevation 2 to 3 folds from baseline (1.0 mg/kg/day warfarin) and 4 to 5 folds from baseline (1.5 mg/kg/day warfarin) by day 7. Serum creatinine and hematuria elevated by day 7 in a dose-dependent manner. Histologically, 2 of 8 (25%) 5/6NE mice had RBCs in the tubules, and there was acute tubular epithelial cell injury in all warfarin-treated 5/6NE 129S1/SvImJ mice., Conclusions: Our findings suggest that 129S1/SvImJ mouse strain is a more suitable murine model to study ARN than C57BL/6 mouse strain., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: Glomerulonephritis (GN) with crescents and IgA deposits in kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities., Methods: Native kidney biopsies showing glomerular IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between 2010 and 2021. Detailed clinicopathologic features were assessed. One-year clinical follow-up on a subset of cases was obtained., Results: A total of 285 cases were identified, and these clustered into IgA nephropathy (IgAN, n  = 108), Staphylococcus or other infection-associated GN/infection-related GN (SAGN/IRGN, n  = 43), and antineutrophil cytoplasmic antibody-associated GN (ANCA-GN, n  = 26) based on a constellation of clinicopathologic features, but 101 cases (group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinicopathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases) revealed that clinicians' working diagnosis was IgAN in 43%, SAGN/IRGN in 22%, ANCA-GN in 28%, and others in 7% of the cases, but treatment approach varied from supportive or antibiotics to immunosuppression in each subgroup. Comparing these cases as "received immunosuppression" versus "non-immunosuppression," only 2 features differed, namely C3-dominant staining, and possibility of recent infection (both higher in the no-immunosuppression group) ( P  < 0.05). Renal loss was higher in the non-immunosuppression subgroup, but not statistically significant ( P  = 0.11)., Conclusion: Diagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery., (© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Introduction: Staphylococcus infection-associated glomerulonephritis (SAGN), is an autoimmune sequela of infection affecting a subset of infected patients without specific predictive factors, frequently presenting with acute nephritic syndrome and propensity for chronic kidney disease. We performed a comparative genotypic and phenotypic analysis of S. aureus isolates from patients that did and those that did not develop SAGN., Methods: We had 22 culture-proven cases of SAGN from Ohio State University Wexner Medical Center (OSUWMC) from 2004 to 2016, 9 of 22 being blood cultures, with archived isolates. These, along with blood culture isolates from 12 patients with no clinical evidence of SAGN (between ages 40 to 80 years) over the same period were used for genotyping. For host demographic comparison, we used all available SAGN cases ( n  = 85, including those with positive cultures other than blood; and patients with kidney biopsies received from referring hospitals) and all OSUWMC patients with positive Staphylococcus cultures without glomerulonephritis (GN) ( n  = 23,496)., Results: Multiple sequence types (STs) suggesting strain diversity was seen in the GN isolates with mainly clonal complexes (CC) 5 and 59. Mutations in the agr operon were identified in significantly higher number of the GN isolates (83%) than non-GN isolates (16%). Significant differences in β-hemolysis and biofilm formation was also observed between the groups., Conclusion: The functionality of these agr mutants remains to be seen, but the presently known effects of reduced agr function, namely increased surface adhesins, biofilm formation, and persistent bacteremia could be important microbial factors predisposing to SAGN and testing for them early during infection could help to predict its development., (© 2022 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

A 60-year-old woman with a past medical history of asthma presented with fulminant myocarditis 9 days after testing positive for SARS-CoV-2 and 16 days after developing symptoms consistent with COVID-19. Her hospital course was complicated by the need for veno-arterial extracorporeal membrane oxygenation, ventricular arrhythmias, and pseudomonas bacteremia. She ultimately recovered and was discharged to home with normal left ventricular systolic function. Thereafter, she developed symptomatic ventricular tachycardia, for which she received an implantable cardioverter-defibrillator and antiarrhythmic drug therapy., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 by the American College of Cardiology Foundation. Published by Elsevier.)

For over a century, acute 'post-streptococcal glomerulonephritis' (APSGN) was the prototypical form of bacterial infection-associated glomerulonephritis, typically occurring after resolution of infection and a distinct infection-free latent period. Other less common forms of infection-associated glomerulonephritides resulted from persistent bacteraemia in association with subacute bacterial endocarditis and shunt nephritis. However, a major paradigm shift in the epidemiology and bacteriology of infection-associated glomerulonephritides has occurred over the past few decades. The incidence of APSGN has sharply declined in the Western world, whereas the number of Staphylococcus infection-associated glomerulonephritis (SAGN) cases increased owing to a surge in drug-resistant Staphylococcus aureus infections, both in the hospital and community settings. These Staphylococcus infections range from superficial skin infections to deep-seated invasive infections such as endocarditis, which is on the rise among young adults owing to the ongoing intravenous drug use epidemic. SAGN is markedly different from APSGN in terms of its demographic profile, temporal association with active infection and disease outcomes. The diagnosis and management of SAGN is challenging because of the lack of unique histological features, the frequently occult nature of the underlying infection and the older age and co-morbidities in the affected patients. The emergence of multi-drug-resistant bacterial strains further complicates patient treatment.

Background and Objectives: Staphylococcus infection-associated GN (SAGN) is a well recognized disease entity, particularly because of the frequent IgA-dominant glomerular immunoglobulin staining on kidney biopsy. Biopsy features can resemble two other disease entities - primary IgA nephropathy and Henoch-Schönlein purpura nephritis - posing a diagnostic pitfall. This is clinically relevant because of the crucial difference in the therapeutic approach. The diagnosis of SAGN is further complicated by the variability in the degree of glomerular IgA (and C3) staining, the extent of electron dense immune-type deposits, and positive ANCA serology in some patients., Design, Setting, Participants, & Measurements: We performed a thorough histopathologic review of our single-center cohort of 78 culture-proven SAGN biopsies to assess the spectrum of IgA staining, prevalence of ANCA serology, prevalence of subepithelial "humps," and other histologic features to distinguish from primary IgA nephropathy., Results: Among the 78 SAGN biopsies, IgA staining was trace in 25%, mild in 19%, moderate in 44%, and strong in 12% of the cases. C3 was frequently moderate-to-strong but was trace in 14% of the biopsies. Concomitantly trace IgA, IgG, and C3 (pauci-immune pattern) was seen in 13%. Crescents were present in 35% of the SAGN biopsies. Out of 41 patients tested for ANCA, nine (22%) were positive, including patients with endocarditis and other infections. Subepithelial humps were identified in only 31% of the SAGN biopsies., Conclusions: SAGN biopsies show marked variability in IgA immunofluorescence staining and low frequency of subepithelial humps compared with poststreptococcal GN. Occasional ANCA positivity is present in cases of SAGN, even in infections other than endocarditis. Therefore, biopsy diagnosis can be difficult particularly when clinical symptoms of infection are subtle. Both the pathologist and the nephrologist should be aware of these diagnostic pitfalls., (Copyright © 2016 by the American Society of Nephrology.)

Owing to the need of lifelong immunosuppression, solid-organ transplant recipients are known to have an increased risk of posttransplant malignancies including lung cancer. Posttransplant neoplastic transformation of donor-derived cells giving rise to hematopoietic malignancies, Kaposi sarcoma, and basal cell carcinoma in nongraft tissues has been reported. The goal of this study was to assess the cell origin (donor versus recipient derived) of posttransplant non-small cell lung carcinomas (NSCLCs) in kidney and heart transplant recipients. An institutional database search identified 2557 kidney and heart transplant recipients in 8 consecutive years. Among this cohort, 20 (0.8%) renal and 18 (0.7%) heart transplant recipients developed NSCLC. The study cohort comprised 6 of 38 NSCLCs arising in donor-recipient sex-mismatched transplant patients. The tumor cell origin was evaluated by chromogenic in situ hybridization with Y-chromosome probe on formalin-fixed, paraffin-embedded tissues. Y-chromosome was identified in 97% ± 1% (range from 92% to 99%) of all types of nucleated cells in male control tissues. In all 5 NSCLCs from male recipients of female donor organ, Y-chromosome was identified in 97% ± 2% (range from 92% to 100%) of tumor cells, statistically equivalent to normal control (P < .001). No Y-chromosome was identified in NSCLC cells from a female recipient of male kidney. These findings suggest a recipient derivation of NSCLC arising in kidney and heart transplant recipients. A combination of histologic evaluation and chromogenic in situ hybridization with Y-chromosome analysis allows reliable determination of tissue origin in sex-mismatched solid-organ transplant recipients and may aid in management of posttransplant malignancy in such cases., (Copyright © 2014 Elsevier Inc. All rights reserved.)