81 results on '"Arend LJ"'
Search Results
2. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.
- Author
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Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand JA, Rosenblatt J, and Sanz I
- Abstract
OBJECTIVE: Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE. METHODS: A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy. RESULTS: Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/microl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t-test). This improvement persisted for 12 months, despite the absence of a significant change in anti-double-stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level > or =100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion. CONCLUSION: Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted. [ABSTRACT FROM AUTHOR]
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- 2004
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3. Clinicopathological characteristics of pediatric ANCA-associated glomerulonephritis.
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Charnaya O, Kruglyakova J, Jacob B, and Arend LJ
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- Humans, Female, Male, Retrospective Studies, Adolescent, Child, Risk Factors, Biopsy, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis pathology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis mortality, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis diagnosis, Kidney pathology, Kidney immunology, Antibodies, Antineutrophil Cytoplasmic blood, Antibodies, Antineutrophil Cytoplasmic immunology, Renal Insufficiency etiology, Immunosuppressive Agents therapeutic use, Proteinuria etiology, Glomerulonephritis pathology, Glomerulonephritis immunology, Glomerulonephritis mortality
- Abstract
Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and glomerulonephritis is uncommon in children. We sought to characterize the histological and clinical features of the disease and report on risk factors for adverse outcomes in a pediatric cohort., Methods: Retrospective single-center cohort of all pediatric (< 20 years) patients diagnosed with ANCA-associated glomerulonephritis (AAGN) by kidney biopsy between 2002 and 2022 at Johns Hopkins University. Histological and clinical features were extracted from the medical record. Clinical, laboratory, and histological findings were analyzed to determine the association with kidney failure (KF) and/or death., Results: A total of 17 patients were identified (GPA n = 7, MPA = 10) with a median age of 15 years (IQR 12-17) at presentation, a slight female predominance (59%), with seven patients reaching the composite outcome of death (n = 1) or kidney failure (n = 6). There was no difference in presenting clinical symptoms or extra-renal manifestations between the two groups. Univariable Cox regression identified several factors associated with an increased hazard of endpoint including the degree of global or segmental sclerosis, interstitial fibrosis and tubular atrophy (IFTA), C3 and C1q staining, presence of subendothelial deposits, and proteinuria. Multivariable regression was not performed due to the small sample size. We saw a trend towards increased utilization of plasma exchange and a decrease in cyclophosphamide utilization in the more recent era. There was no association between treatment modality and outcome., Conclusions: Pediatric AAGN is a rare disease associated with significant morbidity. We identified glomerulosclerosis and IFTA on histology, and proteinuria on initial presentation as risk factors for KF/death., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)
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- 2024
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4. Diagnostic dilemma: drug-induced vasculitis versus systemic vasculitis.
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Acharya I, Weisman DS, Smith LW, and Arend LJ
- Abstract
Competing Interests: Competing interests: None declared.
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- 2024
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5. Double-negative T cells have a reparative role after experimental severe ischemic acute kidney injury.
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Lee K, Gharaie S, Kurzhagen JT, Newman-Rivera AM, Arend LJ, Noel S, and Rabb H
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- Animals, Male, Disease Models, Animal, Fibrosis, Epithelial Cells metabolism, Epithelial Cells pathology, Adoptive Transfer, Mice, Kidney pathology, Kidney immunology, Kidney metabolism, Phenotype, Kidney Tubules pathology, Kidney Tubules metabolism, Regeneration, Cells, Cultured, Acute Kidney Injury immunology, Acute Kidney Injury pathology, Acute Kidney Injury metabolism, Acute Kidney Injury physiopathology, Reperfusion Injury immunology, Reperfusion Injury pathology, Reperfusion Injury metabolism, Mice, Inbred C57BL, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Glomerular Filtration Rate
- Abstract
T cells mediate organ injury and repair. A proportion of unconventional kidney T cells called double-negative (DN) T cells (TCR
+ CD4- CD8- ), with anti-inflammatory properties, were previously demonstrated to protect from early injury in moderate experimental acute kidney injury (AKI). However, their role in repair after AKI has not been studied. We hypothesized that DN T cells mediate repair after severe AKI. C57B6 mice underwent severe (40 min) unilateral ischemia-reperfusion injury (IRI). Kidney DN T cells were studied by flow cytometry and compared with gold-standard anti-inflammatory CD4+ regulatory T cells (Tregs). In vitro effects of DN T cells and Tregs on renal tubular epithelial cell (RTEC) repair after injury were quantified with live-cell analysis. DN T cells, Tregs, CD4, or vehicle were adoptively transferred after severe AKI. Glomerular filtration rate (GFR) was measured using fluorescein isothiocyanate (FITC)-sinistrin. Fibrosis was assessed with Masson's trichrome staining. Profibrotic genes were measured with qRT-PCR. Percentages and the numbers of DN T cells substantially decreased during repair phase after severe AKI, as well as their activation and proliferation. Both DN T cells and Tregs accelerated RTEC cell repair in vitro. Post-AKI transfer of DN T cells reduced kidney fibrosis and improved GFR, as did Treg transfer. DN T cell transfer lowered transforming growth factor (TGF)β1 and α-smooth muscle actin (αSMA) expression. DN T cells reduced effector-memory CD4+ T cells and IL-17 expression. DN T cells undergo quantitative and phenotypical changes after severe AKI, accelerate RTEC repair in vitro as well as improve GFR and renal fibrosis in vivo. DN T cells have potential as immunotherapy to accelerate repair after AKI. NEW & NOTEWORTHY Double-negative (DN) T cells (CD4- CD8- ) are unconventional kidney T cells with regulatory abilities. Their role in repair from acute kidney injury (AKI) is unknown. Kidney DN T cell population decreased during repair after ischemic AKI, in contrast to regulatory T cells (Tregs) which increased. DN T cell administration accelerated tubular repair in vitro, while after severe in vivo ischemic injury reduced kidney fibrosis and increased glomerular filtration rate (GFR). DN T cell infusion is a potential therapeutic agent to improve outcome from severe AKI.- Published
- 2024
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6. Single Nucleus RNA Sequencing of Remnant Kidney Biopsies and Urine Cell RNA Sequencing Reveal Cell Specific Markers of Covid-19 Acute Kidney Injury.
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Ghag R, Kaushal M, Nwanne G, Knoten A, Kiryluk K, Rosenberg A, Menez S, Bagnasco SM, Sperati CJ, Atta MG, Gaut JP, Williams JC, El-Achkar TM, Arend LJ, Parikh CR, and Jain S
- Abstract
Acute kidney injury (AKI) in COVID-19 patients is associated with high mortality and morbidity. Critically ill COVID-19 patients are at twice the risk of in-hospital mortality compared to non-COVID AKI patients. We know little about the cell-specific mechanism in the kidney that contributes to worse clinical outcomes in these patients. New generation single cell technologies have the potential to provide insights into physiological states and molecular mechanisms in COVID-AKI. One of the key limitations is that these patients are severely ill posing significant risks in procuring additional biopsy tissue. We recently generated single nucleus RNA-sequencing data using COVID-AKI patient biopsy tissue as part of the human kidney atlas. Here we describe this approach in detail and report deeper comparative analysis of snRNAseq of 4 COVID-AKI, 4 reference, and 6 non-COVID-AKI biopsies. We also generated and analyzed urine transcriptomics data to find overlapping COVID-AKI-enriched genes and their corresponding cell types in the kidney from snRNA-seq data. We identified all major and minor cell types and states by using by using less than a few cubic millimeters of leftover tissue after pathological workup in our approach. Differential expression analysis of COVID-AKI biopsies showed pathways enriched in viral response, WNT signaling, kidney development, and cytokines in several nephron epithelial cells. COVID-AKI profiles showed a much higher proportion of altered TAL cells than non-COVID AKI and the reference samples. In addition to kidney injury and fibrosis markers indicating robust remodeling we found that, 17 genes overlap between urine cell COVID-AKI transcriptome and the snRNA-seq data from COVID-AKI biopsies. A key feature was that several of the distal nephron and collecting system cell types express these markers. Some of these markers have been previously observed in COVID-19 studies suggesting a common mechanism of injury and potentially the kidney as one of the sources of soluble factors with a potential role in disease progression., Translational Statement: The manuscript describes innovation, application and discovery that impact clinical care in kidney disease. First, the approach to maximize use of remnant frozen clinical biopsies to inform on clinically relevant molecular features can augment existing pathological workflow for any frozen tissue without much change in the protocol. Second, this approach is transformational in medical crises such as pandemics where mechanistic insights are needed to evaluate organ injury, targets for drug therapy and diagnostic and prognostic markers. Third, the cell type specific and soluble markers identified and validated can be used for diagnoses or prognoses in AKI due to different etiologies and in multiorgan injury.
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- 2023
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7. Ichthyosis in sarcoidosis: a rare skin manifestation of a systemic disease.
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Hanouneh M and Arend LJ
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- Humans, Ichthyosis etiology, Sarcoidosis complications, Sarcoidosis diagnosis
- Abstract
Competing Interests: Declaration of interests We declare no competing interests.
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- 2023
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8. Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosis.
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Gharaie S, Lee K, Newman-Rivera AM, Xu J, Patel SK, Gooya M, Arend LJ, Raj DS, Pluznick J, Parikh C, Noel S, and Rabb H
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- Animals, Mice, Kidney pathology, Ischemia, Fibrosis, Amoxicillin adverse effects, Acute Kidney Injury chemically induced, Reperfusion Injury pathology, Microbiota
- Abstract
Targeting gut microbiota has shown promise to prevent experimental acute kidney injury (AKI). However, this has not been studied in relation to accelerating recovery and preventing fibrosis. Here, we found that modifying gut microbiota with an antibiotic administered after severe ischemic kidney injury in mice, particularly with amoxicillin, accelerated recovery. These indices of recovery included increased glomerular filtration rate, diminution of kidney fibrosis, and reduction of kidney profibrotic gene expression. Amoxicillin was found to increase stool Alistipes, Odoribacter and Stomatobaculum species while significantly depleting Holdemanella and Anaeroplasma. Specifically, amoxicillin treatment reduced kidney CD4
+ T cells, interleukin (IL)-17+ CD4+ T cells, and tumor necrosis factor-α double negative T cells while it increased CD8+ T cells and PD1+ CD8+ T cells. Amoxicillin also increased gut lamina propria CD4+ T cells while decreasing CD8+ T and IL-17+ CD4+ T cells. Amoxicillin did not accelerate repair in germ-free or CD8-deficient mice, demonstrating microbiome and CD8+ T lymphocytes dependence for amoxicillin protective effects. However, amoxicillin remained effective in CD4-deficient mice. Fecal microbiota transplantation from amoxicillin-treated to germ-free mice reduced kidney fibrosis and increased Foxp3+ CD8+ T cells. Amoxicillin pre-treatment protected mice against kidney bilateral ischemia reperfusion injury but not cisplatin-induced AKI. Thus, modification of gut bacteria with amoxicillin after severe ischemic AKI is a promising novel therapeutic approach to accelerate recovery of kidney function and mitigate the progression of AKI to chronic kidney disease., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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9. Evaluation of Plasma Biomarkers to Predict Major Adverse Kidney Events in Hospitalized Patients With COVID-19.
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Menez S, Coca SG, Moledina DG, Wen Y, Chan L, Thiessen-Philbrook H, Obeid W, Garibaldi BT, Azeloglu EU, Ugwuowo U, Sperati CJ, Arend LJ, Rosenberg AZ, Kaushal M, Jain S, Wilson FP, and Parikh CR
- Subjects
- Humans, Prospective Studies, Kidney, Biomarkers, Risk Factors, COVID-19 complications, Acute Kidney Injury epidemiology
- Abstract
Rationale & Objective: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19., Study Design: Prospective cohort study., Setting & Participants: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers., Exposure: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization., Outcome: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days., Analytical Approach: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index., Results: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively., Limitations: No control group of hospitalized patients without COVID-19., Conclusions: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes., Plain-Language Summary: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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10. Diagnostic dilemma: drug-induced vasculitis versus systemic vasculitis.
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Acharya I, Weisman DS, Smith LW, and Arend LJ
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- Humans, Hydralazine adverse effects, Kidney pathology, Antibodies, Antineutrophil Cytoplasmic, Glomerulonephritis chemically induced, Glomerulonephritis diagnosis, Lung Diseases etiology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis chemically induced, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis diagnosis, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications
- Abstract
Drug-induced vasculitis can rarely cause inflammation and necrosis of blood vessel walls of both kidney and lung tissue. Diagnosis is challenging because of the lack of difference between systemic and drug-induced vasculitis in clinical presentation, immunological workup and pathological findings. Tissue biopsy guides diagnosis and treatment. Pathological findings must be correlated with clinical information to arrive at a presumed diagnosis of drug-induced vasculitis. We present a patient with hydralazine-induced antineutrophil cytoplasmic antibodies-positive vasculitis with a pulmonary-renal syndrome manifesting as pauci-immune glomerulonephritis and alveolar haemorrhage., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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11. T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.
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Lee K, Thompson EA, Gharaie S, Patel CH, Kurzhagen JT, Pierorazio PM, Arend LJ, Thomas AG, Noel S, Slusher BS, and Rabb H
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- Humans, Mice, Animals, Mice, Inbred C57BL, T-Lymphocyte Subsets metabolism, Ischemia drug therapy, Glutamine, Acute Kidney Injury metabolism
- Abstract
T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57BL/6J mice and collected kidneys and spleens at multiple time points. T cells were isolated and analyzed by an immune-metabolic assay. Unbiased machine learning analyses identified a distinct T cell subset with reduced voltage-dependent anion channel 1 and mTOR expression in post-AKI kidneys. Ischemic kidneys showed higher expression of trimethylation of histone H3 lysine 27 and glutaminase. Splenic T cells from post-AKI mice had higher expression of glucose transporter 1, hexokinase II, and carnitine palmitoyltransferase 1a. Human nonischemic and ischemic kidney tissue displayed similar findings to mouse kidneys. Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist, JHU083, effects on AKI were evaluated. JHU083 attenuated renal injury and reduced T cell activation and proliferation in ischemic and nephrotoxic AKI, whereas T cell-deficient mice were not protected by glutamine blockade. In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach.
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- 2023
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12. Acute kidney injury following methotrexate treatment.
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Donaldson Dasgupta A, Schretlen C, Atta MG, and Arend LJ
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- Humans, Methotrexate adverse effects, Kidney, Acute Kidney Injury chemically induced, Acute Kidney Injury diagnosis, Nephritis, Interstitial
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- 2023
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13. Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI.
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Noel S, Lee K, Gharaie S, Kurzhagen JT, Pierorazio PM, Arend LJ, Kuchroo VK, Cahan P, and Rabb H
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- Humans, Mice, Animals, CD4-Positive T-Lymphocytes, Kidney pathology, Mice, Knockout, Ischemia pathology, Receptors, Immunologic genetics, Immune Checkpoint Proteins, Acute Kidney Injury pathology
- Abstract
Significance Statement: T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials., Background: T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes., Methods: TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans., Results: RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice., Conclusions: TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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14. T Cell Nrf2/Keap1 Gene Editing Using CRISPR/Cas9 and Experimental Kidney Ischemia-Reperfusion Injury.
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Kurzhagen JT, Noel S, Lee K, Sadasivam M, Gharaie S, Ankireddy A, Lee SA, Newman-Rivera A, Gong J, Arend LJ, Hamad ARA, Reddy SP, and Rabb H
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- Mice, Animals, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, CRISPR-Cas Systems, Glutamate-Cysteine Ligase genetics, Glutamate-Cysteine Ligase metabolism, Gene Editing, Kidney metabolism, Oxidative Stress, Antioxidants metabolism, Reperfusion Injury genetics, Reperfusion Injury therapy, Reperfusion Injury metabolism
- Abstract
Aims: T cells play pathophysiologic roles in kidney ischemia-reperfusion injury (IRI), and the nuclear factor erythroid 2-related factor 2/kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway regulates T cell responses. We hypothesized that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated Keap1 -knockout (KO) augments Nrf2 antioxidant potential of CD4+ T cells, and that Keap1 -KO CD4+ T cell immunotherapy protects from kidney IRI. Results: CD4+ T cell Keap1 -KO resulted in significant increase of Nrf2 target genes NAD(P)H quinone dehydrogenase 1, heme oxygenase 1, glutamate-cysteine ligase catalytic subunit, and glutamate-cysteine ligase modifier subunit. Keap1 -KO cells displayed no signs of exhaustion, and had significantly lower levels of interleukin 2 (IL2) and IL6 in normoxic conditions, but increased interferon gamma in hypoxic conditions in vitro . In vivo , adoptive transfer of Keap1 -KO CD4+ T cells before IRI improved kidney function in T cell-deficient nu/nu mice compared with mice receiving unedited control CD4+ T cells. Keap1 -KO CD4+ T cells isolated from recipient kidneys 24 h post IR were less activated compared with unedited CD4+ T cells, isolated from control kidneys. Innovation: Editing Nrf2/Keap1 pathway in murine T cells using CRISPR/Cas9 is an innovative and promising immunotherapy approach for kidney IRI and possibly other solid organ IRI. Conclusion: CRISPR/Cas9-mediated Keap1 -KO increased Nrf2-regulated antioxidant gene expression in murine CD4+ T cells, modified responses to in vitro hypoxia and in vivo kidney IRI. Gene editing targeting the Nrf2/Keap1 pathway in T cells is a promising approach for immune-mediated kidney diseases.
- Published
- 2023
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15. Persistent Isolated C3 Hypocomplementemia as a Strong Predictor of End-Stage Kidney Disease in Lupus Nephritis.
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Rossi GM, Maggiore U, Peyronel F, Fenaroli P, Delsante M, Benigno GD, Gianfreda D, Urban ML, Manna Z, Arend LJ, Bagnasco S, Vaglio A, Fiaccadori E, Rosenberg AZ, Hasni S, and Manenti L
- Abstract
Introduction: Proliferative lupus nephritis (LN) progresses to end-stage kidney disease (ESKD) in roughly 10% of the cases despite treatment. Other than achieving <0.8 g/24h proteinuria at 12 months after treatment, early biomarkers predicting ESKD or death are lacking. Recent studies encompassing not only LN have highlighted the central role of the alternative complement pathway (ACP), with or without histological evidence of thrombotic microangiopathy (TMA), as a key promotor of renal death., Methods: We assessed whether persistent isolated C3 hypocomplementemia (PI-LowC3), that is not accompanied by C4 hypocomplementemia, 6 months after kidney biopsy, is associated with an increased risk of death or ESKD in proliferative LN., Results: We retrospectively followed-up 197 patients with proliferative LN (51 with PI-LowC3) for a median of 4.5 years (interquartile-range: 1.9-9.0), 11 of whom died and 22 reached ESKD. After adjusting for age, gender, ethnicity, hypertension, mycophenolate, or cyclophosphamide use, PI-LowC3 was associated with a hazard ratio [HR] of the composite outcome ESKD or death of 2.46 (95% confidence interval [CI]: 1.22-4.99, P = 0.012). These results were confirmed even after controlling for time-varying estimated glomerular filtration rate (eGFR) measurements in joint longitudinal-survival multiple regression models. After accounting for the competing risk of death, PI-LowC3 patients showed a strikingly increased risk of ESKD (adjusted HR 3.41, 95% CI: 1.31-8.88, P = 0.012)., Conclusion: Our findings support the use of PI-LowC3 as a low-cost readily available biomarker, allowing clinicians to modify treatment strategies early in the course of disease and offering a rationale for complement blockade trials in this particularly at-risk subgroup of LN patients., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2022
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16. Characterization of interstitial infiltrates in MPO and PR3 anti-neutrophil cytoplasmic antibody glomerulonephritis.
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Kant S, Arend LJ, Gapud E, Seo P, and Geetha D
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- Antibodies, Antineutrophil Cytoplasmic, Female, Forkhead Transcription Factors, Humans, Kidney pathology, Male, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Glomerulonephritis metabolism
- Abstract
Introduction: It has been recognized that T cells have a pathogenic role in anti-neutrophil cytoplasmic antibody- (ANCA) associated vasculitis, in addition to being dominant cells in the interstitium in ANCA glomerulonephritis (GN). Given there are differences in renal outcomes based on ANCA type, we sought to characterize the interstitial infiltrate in ANCA GN to determine differences in relation to ANCA type and renal function., Methods: Immunohistochemistry stains for CD3, CD4, CD20, C4d and FOXP3 were done in renal biopsies of patients with ANCA GN. Light microscopy was used to determine the percentage of cortical interstitium containing positive cells. Demographics, ANCA type and entry eGFR were recorded. The level of staining was compared between ANCA type and entry eGFR using Wilcoxon rank-sum test., Results: Renal biopsies of 16 patients with MPO and 14 with PR3 ANCA GN were studied. CD3 cells were the predominant cells, with all biopsies staining positive for CD4 and FOXP3. C4d staining was negative in all biopsies, with no significant difference in staining between MPO and PR3 groups for any of the identified cell types. However, regardless of ANCA type, FOXP3 staining was significantly higher in patients with baseline GFR < 10 compared with GFR > 10 mL/min/1.73 m
2 (mean 7.54, SD 6.6 versus mean 2.67, SD 3.6; p = 0.04)., Conclusion: These data confirm the role of T cells in ANCA GN and demonstrate no differences in interstitial T and B cell infiltrates between PR3 and MPO ANCA GN. Higher FOXP3 signal associates with lower renal function, suggesting a role for regulatory T cells. Further characterization of this T cell subset should be explored in future studies., (© 2021. Italian Society of Nephrology.)- Published
- 2022
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17. The Prevalence of Mesangial Electron-Dense Deposits in PLA2R-Positive Membranous Nephropathy.
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Giannini G and Arend LJ
- Subjects
- Adult, Autoantibodies, Electrons, Humans, Prevalence, Glomerulonephritis, Membranous complications, Receptors, Phospholipase A2
- Abstract
Introduction: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and can be primary or secondary. The antigenic target of antibodies in 70% of primary cases is phospholipase A2 receptor (PLA2R). The presence or absence of mesangial electron-dense deposits has been used to distinguish between primary and secondary MN. Mesangial deposits suggest MN due to lupus, infection, or other causes, though they are reported to occur in approximately 10% of primary MN. Staining for PLA2R is now frequently used for confirming a diagnosis of primary MN. If mesangial deposits predict a secondary cause, they should be more frequent in PLA2R-negative biopsies., Methods: A review of institutional kidney biopsies between March 2017 and June 2020 identified all cases of MN. Cases with a diagnosis of lupus or near "full-house" staining by immunofluorescence microscopy (IF) were excluded. Light microscopy, IF, and electron microscopy (EM) were performed. PLA2R staining was performed by IF. EM for all cases was reviewed and electron-dense deposit location, distribution, and size were determined., Results: Ninety-three cases of MN were identified, of which 86 had both PLA2R staining and EM performed. Of these, 51 cases (59%) were positive for PLA2R and 35 (41%) were negative. Mesangial electron-dense deposits were present in 22 (25.6%) of the 86 cases, including 27.5% (14/51) of PLA2R-positive cases and 22.8% (8/35) of PLA2R-negative cases. No difference was seen in size or distribution of deposits, or other features considered suggestive of secondary MN., Conclusion: PLA2R-negative cases were not more likely to have mesangial deposits than PLA2R-positive cases. Mesangial deposits should not be used as an indicator of secondary MN., (© 2021 S. Karger AG, Basel.)
- Published
- 2022
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18. Quality assurance: Evaluation and comparison of methods for electron microscopic measurement of GBM width and the effect of in-lab calibration in diagnostic renal pathology.
- Author
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Uner M, Demirkol Canlı S, and Arend LJ
- Subjects
- Calibration, Electrons, Humans, Kidney, Microscopy, Electron, Glomerular Basement Membrane, Laboratories
- Abstract
Replacing equipment and software can improve efficiency and allow updates to laboratory procedures, but has the potential to introduce changes in established values for a laboratory. Replacement of an electron microscope (EM), fitted with an updated digital camera, and use of new software for imaging and analysis prompted this QA study to ensure that new equipment, imaging, and measurement of the glomerular basement membrane (GBM) produced data consistent with the laboratory's established range of normal width. GBM measurements from 14 randomly selected human renal biopsies were compared using five different approaches. Original measurements of GBMs obtained on the laboratory's previous EM were compared to images collected on the new microscope with measurements performed using new software, as well as the original images and the new images measured using a separate software method as a control. The widths obtained by five approaches were compared to each other. While measurements showed minor variability between the approaches, significant difference in GBM width was noted in three of the paired comparisons. In some cases, these differences suggested slight diagnostic changes. Evaluation of new equipment, software, and techniques is important for a laboratory's quality assurance. While new equipment and/or procedures can introduce errors in test outcomes, we found that different EMs, cameras, and software made slight differences in our laboratory's values for kidney GBM width. However, a few cases showed enough difference in GBM width to suggest a change in diagnosis, illustrating the necessity of calibration adjustments in the setting of new equipment and software., (© 2021 Wiley Periodicals LLC.)
- Published
- 2022
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19. Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans.
- Author
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Watanabe H, Martini AG, Brown RI, Liang X, Medrano S, Goto S, Narita I, Arend LJ, Sequeira-Lopez MLS, and Gomez RA
- Subjects
- Animals, Humans, Mice, Hypertension physiopathology, Kidney blood supply, Renin-Angiotensin System physiology
- Abstract
Inhibitors of the renin-angiotensin system (RAS) are widely used to treat hypertension. Using mice harboring fluorescent cell lineage tracers, single-cell RNA-Seq, and long-term inhibition of RAS in both mice and humans, we found that deletion of renin or inhibition of the RAS leads to concentric thickening of the intrarenal arteries and arterioles. This severe disease was caused by the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype: the cells surrounded the vessel walls and induced the accumulation of adjacent smooth muscle cells and extracellular matrix, resulting in blood flow obstruction, focal ischemia, and fibrosis. Ablation of the renin cells via conditional deletion of β1 integrin prevented arteriolar hypertrophy, indicating that renin cells are responsible for vascular disease. Given these findings, prospective morphological studies in humans are necessary to determine the extent of renal vascular damage caused by the widespread use of inhibitors of the RAS.
- Published
- 2021
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20. Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus.
- Author
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Alkhatib MH, Kant S, Menez S, Lakhani L, Sperati CJ, Fine DM, Arend LJ, and Atta MG
- Subjects
- Humans, Kidney, Retrospective Studies, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic diagnosis, Lupus Nephritis diagnosis, Thrombotic Microangiopathies diagnosis, Thrombotic Microangiopathies etiology
- Abstract
Background: Kidney involvement is common in patients with systemic lupus erythematosus (SLE). This study investigates the clinical and prognostic characteristics of thrombotic microangiopathy (TMA) compared to class IV lupus nephritis in SLE patients., Methods: A retrospective review of patients who underwent kidney biopsy, with a primary diagnosis of SLE and TMA between June 2006 and September 2018 was conducted. Those patients were subsequently compared to patients with class IV lupus nephritis between January 2018 and December 2018. Demographics, laboratory, and serological data at the time of biopsy were abstracted., Results: Among 214 SLE patients records screened, 27 were included in the final analysis. Eight patients had lupus-related TMA without evidence of active lupus nephritis, while 19 patients had class IV lupus nephritis without evidence of TMA. TMA patients had significantly higher lactate dehydrogenase levels (718 ± 499 vs. 264 ± 107.7 U/L, p = 0.009), serum C3 (100.6 ± 39.3 vs. 65.8 ± 27 mg/dL, p = 0.049), white blood cell count (14743.8 ± 7933.3 vs. 5807.9 ± 2053.2 × 10E3/uL, p < 0.001), and total bilirubin (0.8 ± 0.5 vs. 0.3 ± 0.1 mg/dL, p = 0.007) in addition to significantly lower platelet counts (158.4 ± 88.6 vs. 240.3 ± 100.3 × 10E3/uL, p = 0.03), and haptoglobin (68.8 ± 116.1 vs. 166.8 ± 95.4 mg/dL, p = 0.03). After a median follow-up time of 53 weeks, 3 patients with TMA were dialysis-dependent (37.5%), compared with none in class IV lupus nephritis patients (p = 0.002)., Conclusions: TMA-associated SLE has worse prognosis compared to class IV lupus nephritis. An array of laboratory and pathological findings may be of value in discriminating between those two entities., (© 2021. Italian Society of Nephrology.)
- Published
- 2021
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21. Facial Swelling and Pancytopenia: First Features and Clues to the Etiology of Acute Kidney Injury.
- Author
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Goetsch MR, Plott C, Woller JA 3rd, Fine DM, Arend LJ, Locke CF, Walker SL, and Gelber AC
- Subjects
- Diagnosis, Differential, Drug Therapy, Combination, Face, Fatigue, Female, Humans, Kidney Function Tests, Middle Aged, Oral Ulcer, Urinalysis, Weight Loss, Edema diagnosis, Lupus Nephritis diagnosis, Lupus Nephritis drug therapy, Pancytopenia diagnosis
- Published
- 2021
- Full Text
- View/download PDF
22. Collagen Type III Glomerulopathy.
- Author
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Wilson AV, Costigliolo F, Farris AB, Rengen R, and Arend LJ
- Published
- 2021
- Full Text
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23. ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
- Author
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Mollaeian A, Chan N, Aloor R, Iding JS, Arend LJ, Saeidabadi SHF, and Haas CJ
- Abstract
Background: Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy., Case Report: A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade., Conclusion: This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
- Published
- 2021
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24. Low-Level Proteinuria in Systemic Lupus Erythematosus.
- Author
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Chedid A, Rossi GM, Peyronel F, Menez S, Atta MG, Bagnasco SM, Arend LJ, Rosenberg AZ, and Fine DM
- Abstract
Introduction: In patients with systemic lupus erythematosus (SLE) without concurrent active urinary sediment or unexplained acute kidney injury (AKI), current guidelines recommend performing a kidney biopsy in those with at least 500 mg/24-hour (European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA]) or 1000 mg/24-hour (American College of Rheumatology [ACR]) proteinuria. To evaluate the relevance of these indications, we studied histopathologic findings in patients with SLE with proteinuria below these cutoffs., Methods: We retrospectively reviewed the clinical, laboratory and histological characteristics of patients with SLE with <1000 mg/24-hour proteinuria (or mg/g urinary protein-to-creatinine ratio [UPCR]) who underwent their first kidney biopsy between 2003 and 2018., Results: We identified 87 patients with SLE with proteinuria less than 1000 mg/24-hour (or mg/g UPCR); 52 of 87 (60%) with isolated proteinuria, that is, without AKI or active urinary sediment (hematuria). Histologic evidence of lupus nephritis (LN) was present in 40 of 52 (76%). Of the 40 patients with LN, 12 had class I or II, 14 had class III or IV, 8 had class V, 6 had a combined proliferative and membranous LN. Non-lupus diagnoses included focal segmental glomerulosclerosis, acute interstitial nephritis, and others. Patient's age, low C3, low C4, and positivity for anti-double-stranded DNA (anti-dsDNA) antibodies predicted the histological diagnosis of LN on univariate logistic regression; however, a multivariate model including these parameters as independent covariates failed to predict LN., Conclusions: Patients with SLE with low-level proteinuria may have significant lupus- or non-lupus-related kidney disease with management implications. There was a significant burden of severe forms of LN. The presence of LN was not predicted by laboratory abnormalities. Based on our findings, we suggest current guidelines be revised to expand kidney biopsy indications to include isolated proteinuria of any grade., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2020
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25. TCR + CD4 - CD8 - (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury.
- Author
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Gong J, Noel S, Hsu J, Bush EL, Arend LJ, Sadasivam M, Lee SA, Kurzhagen JT, Hamad ARA, and Rabb H
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury immunology, Acute Kidney Injury pathology, Animals, B7-H1 Antigen immunology, Cell Proliferation, Cells, Cultured, Coculture Techniques, Disease Models, Animal, Epithelial Cells pathology, Kidney Tubules, Proximal pathology, Male, Mice, Inbred C57BL, Phenotype, T-Lymphocyte Subsets immunology, Acute Kidney Injury prevention & control, Adoptive Transfer, Apoptosis, Cisplatin, Epithelial Cells immunology, Kidney Tubules, Proximal immunology, Receptors, Antigen, T-Cell immunology, T-Lymphocyte Subsets transplantation
- Abstract
Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor
+ CD4- CD8- double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.- Published
- 2020
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26. Crystalglobulin-associated nephropathy presenting as MGRS in a case of monoclonal B-cell lymphocytosis: a case report.
- Author
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Gupta RK, Arend LJ, Bk A, Narsipur S, and Bhargava R
- Subjects
- Acute Kidney Injury blood, Acute Kidney Injury etiology, Acute Kidney Injury pathology, Humans, Kidney Diseases blood, Kidney Diseases diagnosis, Kidney Diseases etiology, Kidney Diseases pathology, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytosis blood, Lymphocytosis complications, Male, Middle Aged, Paraproteinemias blood, Paraproteinemias complications, Acute Kidney Injury diagnosis, B-Lymphocytes, Crystallization, Immunoglobulin Light Chains blood, Immunoglobulin kappa-Chains blood, Kidney pathology, Lymphocytosis diagnosis, Paraproteinemias diagnosis
- Abstract
Background: Crystalglobulin-associated nephropathy (CAN), a rare subtype of monoclonal gammopathy, usually associated with multiple myeloma and occasionally monoclonal gammopathy of uncertain significance (MGUS), is characterized by occluding monoclonal pseudothrombi within renal glomerular capillaries and/or interstitial arterioles. Ultrastructurally, these pseudothrombi are unique for having a crystalline substructure. We describe a case of an adult patient with monoclonal B-cell lymphocytosis (MBL) and acute renal failure whose kidney biopsy revealed a rare diagnosis of CAN., Case Presentation: A 63-year old male presented with a 2-month history of edema, arthralgia and malaise. He had acute kidney injury with hematoproteinuria on urine analysis. Serum and urine protein electrophoresis were both negative. A renal biopsy however revealed features of CAN. Organomegaly, bone pain and lymphadenopathy were absent. A repeat serum electrophoresis was positive for IgA kappa and a free light chain assay showed elevated free kappa light chains. Flow cytometry done subsequently revealed a diagnosis of MBL, chronic lymphocytic leukemia (CLL) type., Conclusion: CAN in association with MBL/CLL has not been previously described in literature, and our case highlights yet another instance of monoclonal gammopathy of renal significance (MGRS) where a small B-cell clone resulted in extensive renal pathology without systemic manifestations.
- Published
- 2020
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27. BK Virus RNA in Renal Allograft Biopsies.
- Author
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Costigliolo F, Lombardo K, Arend LJ, Rosenberg AZ, Matoso A, Carter-Monroe N, and Bagnasco SM
- Subjects
- BK Virus isolation & purification, Biopsy, Cohort Studies, Female, Humans, Kidney pathology, Kidney virology, Male, Middle Aged, Transplantation, Homologous, BK Virus genetics, BK Virus physiology, DNA, Viral genetics, Kidney Transplantation
- Abstract
BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC ( R
2 = 0.65, p< 0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.- Published
- 2020
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28. When the Past Informs the Present: An Exercise in Clinical Reasoning.
- Author
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Manesh R, Geha RM, Dhaliwal G, Heng J, Arend LJ, Fine DM, and Gelber AC
- Subjects
- Clinical Competence, Humans, Thinking, Clinical Reasoning, Exercise
- Published
- 2020
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29. CD4 + T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury.
- Author
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Lee SA, Noel S, Kurzhagen JT, Sadasivam M, Pierorazio PM, Arend LJ, Hamad AR, and Rabb H
- Subjects
- Animals, CD4-Positive T-Lymphocytes transplantation, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Humans, Interferon-gamma genetics, Interferon-gamma metabolism, Kidney pathology, Lipocalin-2 genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Sequence Analysis, RNA, Up-Regulation, Acute Kidney Injury immunology, CD4-Positive T-Lymphocytes immunology, Ischemia immunology, Kidney metabolism, Lipocalin-2 metabolism
- Abstract
CD4
+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4+ T cell-mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 ( Lcn2 ) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest fold increase (∼60). The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with quantitative real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions. However, the role of NGAL produced by CD4+ T cells is not known. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared with wild-type (WT) mice. Adoptive transfer of NGAL - deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro-simulated ischemia/reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared with WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1, and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly after ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics., (Copyright © 2020 by The American Association of Immunologists, Inc.)- Published
- 2020
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30. Renal crystal-storing histiocytosis involving glomeruli - A comprehensive clinicopathologic analysis.
- Author
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Gupta RK, Rosenberg AZ, Bagnasco SM, and Arend LJ
- Subjects
- Adult, Aged, Biopsy, Creatinine blood, Female, Glomerular Mesangium blood supply, Glomerular Mesangium metabolism, Glomerular Mesangium ultrastructure, Glomerulonephritis, Membranous metabolism, Glomerulonephritis, Membranous pathology, Histiocytes metabolism, Histiocytes pathology, Humans, Kidney metabolism, Kidney ultrastructure, Lymphoproliferative Disorders complications, Lymphoproliferative Disorders metabolism, Lymphoproliferative Disorders pathology, Male, Microscopy, Electron methods, Middle Aged, Multiple Myeloma complications, Multiple Myeloma metabolism, Multiple Myeloma pathology, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Myeloma Proteins metabolism, Paraproteinemias pathology, Proteinuria diagnosis, Glomerular Mesangium pathology, Histiocytosis complications, Kidney pathology
- Abstract
Crystal-storing histiocytosis (CSH) is a rare manifestation of monoclonal gammopathy in which histiocytes containing monoclonal proteins in their cytoplasm are found in various organs of the body including the kidney. Within the kidney, these monoclonal crystal-laden histiocytes have been described to occur in the interstitium (most commonly) or in the glomerular mesangium. CSH within glomerular capillary loops has rarely been reported. We describe three cases of CSH primarily affecting the glomerular capillaries and review the literature of CSH in general. Twenty cases of CSH involving the kidney are present in the literature; three describe CSH in glomeruli, only one of which showed histiocytes predominantly in glomerular capillary loops, while 15 had predominantly or solely interstitial CSH. Most cases involve IgG kappa crystals with only one case involving lambda light chain. Patients with CSH predominantly involving the glomerular capillaries showed a trend toward lower serum creatinine and proteinuria at presentation, and several patients with CSH lacked a definitive diagnosis of a monoclonal gammopathy at the time of diagnosis, emphasizing the role that kidney biopsy and particularly electron microscopy play in diagnosis of this entity., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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31. Renal involvement in primary Sjögren's syndrome: natural history and treatment outcome.
- Author
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Goules A, Geetha D, Arend LJ, and Baer AN
- Subjects
- Humans, Kidney, Treatment Outcome, Glomerulonephritis etiology, Glomerulonephritis therapy, Nephritis, Interstitial etiology, Nephritis, Interstitial therapy, Sjogren's Syndrome complications
- Abstract
Objectives: Overt renal disease in primary Sjögren's syndrome (pSS) manifests as interstitial nephritis and glomerulonephritis. This single centre study aims to describe the natural history and treatment outcome of renal disease in pSS., Methods: pSS patients with renal disease were identified, and clinical features, renal biopsy findings, treatment details and renal outcome were recorded., Results: Of the 20 pSS patients with renal disease, 14 had interstitial nephritis (IN), 3 had glomerulonephritis (GN) and 3 had both entities. In the IN group, 3 patients presented with chronic kidney disease (CKD), 4 with renal tubular acidosis (RTA), 2 with symptomatic hypokalaemia, 4 with renal colic and 1 with haematuria/proteinuria. Eight of 14 patients with IN received systemic immunosuppression (IS) during renal disease course and in 6 patients no beneficial effect was observed on renal function, hypokalaemia and RTA. Six of 14 IN patients developed CKD while 5 of them preserved normal renal function during follow-up. In the GN group, 2 patients presented with CKD, 3 with proteinuria/haematuria and 1 with nephrotic proteinuria. GN renal biopsy findings revealed membranoproliferative (MPGN) (n=3), focal segmental glomerulosclerosis (n=1) and fibrillary glomerulopathy (n=1). All 3 MPGN patients had cryoglobulinaemia and in 1 patient cryoglobulinaemic MPGN was clinically diagnosed. All GN patients were treated with immunosuppressive therapy, with stabilisation or improvement of renal function in the 4 cryoglobulinaemia-associated GN patients only., Conclusions: Interstitial nephritis follows a slow course and does not improve with systemic immunosuppression while GN has a favourable treatment response in those with MPGN pathology.
- Published
- 2019
32. Microvascular inflammation in renal allograft biopsies assessed by endothelial and leukocyte co-immunostain: a retrospective study on reproducibility and clinical/prognostic correlates.
- Author
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Delsante M, Maggiore U, Levi J, Kleiner DE, Jackson AM, Arend LJ, Hewitt SM, Carter-Monroe N, Bagnasco SM, and Rosenberg AZ
- Subjects
- Adult, Antigens, CD34 analysis, Biopsy, Female, Humans, Inflammation, Kidney blood supply, Leukocyte Common Antigens analysis, Male, Middle Aged, Prognosis, Reproducibility of Results, Retrospective Studies, Transplantation, Homologous, Endothelium chemistry, Kidney pathology, Kidney Transplantation, Leukocytes chemistry, Microvessels physiology
- Abstract
The most prominent histologic lesion in antibody-mediated rejection is microvascular inflammation (MVI); however, its recognition and scoring can be challenging and poorly reproducible between pathologists. We developed a dual immunohistochemical (IHC)-stain (anti-CD34/anti-CD45 for endothelium/leukocytes) as ancillary tool to improve on the semi-quantitative Banff scores and allow quantification of MVI. We examined the relationship between CD34-CD45 IHC-based quantitative MVI score (the inflamed peritubular capillary ratio, iptcr) and renal-graft failure or donor-specific antibodies (DSA) strength at the time of biopsy. Quantitative iptcr score was significantly associated with renal graft failure (hazard ratio 1.81, per 1 SD-unit [0.13 points] of iptcr-increase; P = 0.026) and predicted the presence and strength of DSA (ordinal odds ratio: 2.42; P = 0.005; 75 biopsies/60 kidney transplant recipients; 30 HLA- and/or ABO-incompatible). Next, we assessed inter-pathologist agreement for ptc score and ptc extent (focal/diffuse) using CD34-CD45 IHC as compared to conventional stain. Compared to conventional stain, CD34-CD45 IHC significantly increased inter-pathologist agreement on ptc score severity and extent (κ-coefficient from 0.52-0.80 and 0.46-0.68, respectively, P < 0.001). Our findings show that CD34-CD45 IHC improves reproducibility of MVI scoring and facilitates MVI quantification and introduction of a dual anti-CD34/CD45 has the potential to improve recognition of MVI ahead of DSA results., (© 2018 Steunstichting ESOT.)
- Published
- 2019
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33. Identifying the localization and exploring a functional role for Gprc5c in the kidney.
- Author
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Rajkumar P, Cha B, Yin J, Arend LJ, Păunescu TG, Hirabayashi Y, Donowitz M, and Pluznick JL
- Subjects
- Acids blood, Acids urine, Alkalies blood, Alkalies urine, Animals, HEK293 Cells, Humans, Kidney Tubules, Proximal physiology, Mice, Mice, Inbred C57BL, Protein Transport, Receptors, G-Protein-Coupled genetics, Sodium-Hydrogen Exchanger 3 metabolism, Water-Electrolyte Balance, Kidney Tubules, Proximal metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
The investigation of orphan GPCRs (GPRs) has the potential to uncover novel insights into whole animal physiology. In this study, our goal was to determine the renal localization of Gprc5c, a receptor that we previously reported to be highly expressed in murine whole kidney, and to examine physiologic parameters in Gprc5c knockout (KO) mice to gain insight into function. Gprc5c localized to the apical membrane of renal proximal tubules (PTs) in mice, rats, and humans. With the comparison of Gprc5c wild-type (WT) and KO mice, we found that Gprc5c KO mice have altered acid-base homeostasis. Specifically, Gprc5c KO mice have lower blood pH and higher urine pH compared with WT mice, with a reduced level of titratable acids in their urine. In an in vitro GPCR internalization assay, we observed that Gprc5c internalization (an index of activation) was triggered by alkaline extracellular pH. Furthermore, with the use of an in vitro BCECF assay, we observed that Gprc5c increases Na
+ /H+ exchanger 3 (NHE3) activity at alkaline pH. We also find that the NHE3 activity is reduced in Gprc5c KO mice by 2 photon imaging in seminaphthorhodafluors (SNARF)-4F-loaded kidney sections. NHE3 is a primary contributor to apical transport of H+ in the renal PT. Together, these data imply that Gprc5c modulates the renal contribution to systemic pH homeostasis, at least in part, by taking part in the regulation of NHE3.-Rajkumar, P., Cha, B., Yin, J., Arend, L. J., Păunescu, T. G., Hirabayashi, Y., Donowitz, M., Pluznick, J. L. Identifying the localization and exploring a functional role for Gprc5c in the kidney.- Published
- 2018
- Full Text
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34. Deletion of Pkd1 in renal stromal cells causes defects in the renal stromal compartment and progressive cystogenesis in the kidney.
- Author
-
Nie X and Arend LJ
- Subjects
- Animals, Apoptosis genetics, Cell Proliferation genetics, Disease Models, Animal, Disease Progression, Mice, Mice, Knockout, Stromal Cells cytology, Stromal Cells metabolism, Kidney cytology, Kidney metabolism, Kidney pathology, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, TRPP Cation Channels genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD), caused by PKD1 and PKD2 gene mutations, is one of the most common genetic diseases, affecting up to 1 in 500 people. Mutations of PKD1 account for over 85% of ADPKD cases. However, mechanisms of disease progression and explanations for the wide range in disease phenotype remain to be elucidated. Moreover, functional roles of PKD1 in the renal stromal compartment are poorly understood. In this work, we tested if Pkd1 is essential for development and maintenance of the renal stromal compartment and if this role contributes to pathogenesis of polycystic kidney disease using a novel tissue-specific knockout mouse model. We demonstrate that deletion of Pkd1 from renal stromal cells using Foxd1-driven Cre causes a spectrum of defects in the stromal compartment, including excessive apoptosis/proliferation and extracellular matrix deficiency. Renal vasculature was also defective. Further, mutant mice showed epithelial changes and progressive cystogenesis in adulthood modeling human ADPKD. Altogether, we provide robust evidence to support indispensable roles for Pkd1 in development and maintenance of stromal cell derivatives by using a novel ADPKD model. Moreover, stromal compartment defects caused by Pkd1 deletion might serve as an important mechanism for pathogenesis of ADPKD.
- Published
- 2017
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35. Successful Renal Transplantation of Deceased Donor Kidneys With 100% Glomerular Fibrin Thrombi and Acute Renal Failure Due to Disseminated Intravascular Coagulation.
- Author
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Soares KC, Arend LJ, Lonze BE, Desai NM, Alachkar N, Naqvi F, and Montgomery RA
- Subjects
- Acute Kidney Injury pathology, Aged, Allografts, Biomarkers analysis, Biopsy, Delayed Graft Function diagnosis, Delayed Graft Function etiology, Delayed Graft Function therapy, Disseminated Intravascular Coagulation pathology, Female, Humans, Kidney Glomerulus chemistry, Kidney Glomerulus pathology, Kidney Transplantation adverse effects, Male, Middle Aged, Predictive Value of Tests, Renal Dialysis, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Young Adult, Acute Kidney Injury etiology, Disseminated Intravascular Coagulation complications, Donor Selection, Fibrin analysis, Kidney Glomerulus transplantation, Kidney Transplantation methods, Tissue Donors supply & distribution
- Abstract
Background: Disseminated intravascular coagulation (DIC)-positive kidneys have historically been turned down for fear of poor outcomes. Higher severity injuries, which are prone to DIC, are typically seen in younger, otherwise healthy potential donors. The continued kidney allograft shortage has generated interest in the use of these DIC-positive grafts. There have been some reports of acceptable outcomes of renal transplantation using kidneys from donors with DIC. There are multiple clinical series demonstrating good outcomes from DIC-positive kidneys when the extent of glomeruli containing fibrin thrombi is less than 50% and donor renal function is preserved. These grafts are frequently associated with a period of delayed graft function., Methods: We report 2 transplants with kidneys from brain dead donors with known DIC., Results: Both donors had renal failure and pretransplant renal biopsies showing 100% of the glomeruli containing fibrin thrombi. The recipients experienced delayed graft function requiring hemodialysis which was discontinued on postoperative days 18 and 39 for cases 1 and 2, respectively. Both patients are now over 14 months posttransplant with stable allograft function., Conclusions: Until clearer organ selection criteria are established, caution should be exercised when considering the use of kidneys with a similar phenotype and allocation decisions made by a multidisciplinary transplant team on a case-by-case basis.
- Published
- 2017
- Full Text
- View/download PDF
36. Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice.
- Author
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Noel S, Arend LJ, Bandapalle S, Reddy SP, and Rabb H
- Subjects
- Animals, Gene Deletion, Hydronephrosis pathology, Kidney growth & development, Kidney pathology, Male, Mice, Mice, Knockout, Mice, Transgenic, Epithelium metabolism, Hydronephrosis genetics, Hydronephrosis metabolism, Kelch-Like ECH-Associated Protein 1 deficiency, Kelch-Like ECH-Associated Protein 1 genetics, Kidney metabolism
- Abstract
Background: Transcription factor Nrf2 protects from experimental acute kidney injury (AKI) and is promising to limit progression in human chronic kidney disease (CKD) by upregulating multiple antioxidant genes. We recently demonstrated that deletion of Keap1, the endogenous inhibitor of Nrf2, in T lymphocytes significantly protects from AKI. In this study, we investigated the effect of Keap1 deletion on Nrf2 mediated antioxidant response in the renal tubular epithelial cells., Methods: We deleted Keap1 exon 2 and 3 in the renal tubular epithelial cells by crossing Ksp-Cre mice with Keap1 floxed (Keap1 (f/f)) mice. Deletion of Keap1 gene in the kidney epithelial cells of Ksp-Keap1 (-/-) mice and its effect on Nrf2 target gene expression was performed using PCR and real-time PCR respectively. Histological evaluation was performed on H&E stained sections. Complete blood count, serum and urine analysis were performed to assess systemic effects of defective kidney development. Student's T test was used to determine statistical difference between the groups., Results: Ksp-Cre resulted in the deletion of Keap1 exon 2 and 3 and subsequent upregulation of Nrf2 target genes, Nqo1, Gclm and Gclc in the kidney epithelial cells of Ksp-Keap1 (-/-) mice at baseline. Renal epithelial cell specific deletion of Keap1 in Ksp-Keap1 (-/-) mice caused marked renal pelvic expansion and significant compression of medullary parenchyma consistent with hydronephrosis in both (3 month-old) males and females. Kidneys from 6 month-old Ksp-Keap1 (-/-) mice showed progressive hydronephrosis. Hematological, biochemical and urinary analysis showed significantly higher red blood cell count (p = 0.04), hemoglobin (p = 0.01), hematocrit (p = 0.02), mean cell volume (p = 0.02) and mean cell hemoglobin concentration (p = 0.003) in Ksp-Keap1 (-/-) mice in comparison to Keap1 (f/f) mice., Conclusions: These unexpected findings demonstrate that Keap1 deletion in renal tubular epithelial cells results in an abnormal kidney development consistent with hydronephrosis and reveals a novel Keap1 mediated signaling pathway in renal development.
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- 2016
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37. Double-Negative αβ T Cells Are Early Responders to AKI and Are Found in Human Kidney.
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Martina MN, Noel S, Saxena A, Bandapalle S, Majithia R, Jie C, Arend LJ, Allaf ME, Rabb H, and Hamad AR
- Subjects
- Animals, CD4 Antigens, CD8 Antigens, Humans, Male, Mice, Mice, Inbred C57BL, Acute Kidney Injury immunology, Kidney immunology, T-Lymphocytes physiology
- Abstract
Ischemia-reperfusion injury (IRI) is a major cause of AKI, and previous studies established important roles for conventional CD4(+) T cells, natural killer T cells, and CD4(+)CD25(+)FoxP3(+) Tregs in AKI pathogenesis. We recently identified CD4(-)CD8(-) (double-negative; DN) T cells as an important subset of αβ T cell receptor-positive cells residing in mouse kidney. However, little is known about the pathophysiologic functions of kidney DN T cells. In this study, we phenotypically and functionally characterized murine kidney DN T cells in the steady state and in response to IRI. Unlike CD4(+) and CD8(+) T cells, DN T cells in the steady state expressed high levels of CD69, CD28, and CD40L; differentially expressed IL-27 and IL-10 anti-inflammatory cytokines; spontaneously proliferated at a very high rate; and suppressed in vitro proliferation of activated CD4(+) T cells. Within the first 3-24 hours after IRI, kidney DN T cells expanded significantly and upregulated expression of IL-10. In adoptive transfer experiments, DN T cells significantly protected recipients from AKI by an IL-10-dependent mechanism. DN T cells also made up a large fraction of the T cell compartment in human kidneys. Our results indicate that DN T cells are an important subset of the resident αβ(+) T cell population in the mammalian kidney and are early responders to AKI that have anti-inflammatory properties., (Copyright © 2016 by the American Society of Nephrology.)
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- 2016
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38. STIM1fl/fl Ksp-Cre Mouse has Impaired Renal Water Balance.
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Cebotaru L, Cebotaru V, Wang H, Arend LJ, and Guggino WB
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- Animals, Calcium blood, Calcium urine, Creatinine blood, Creatinine urine, Dietary Proteins administration & dosage, Dietary Proteins pharmacology, Kidney Concentrating Ability genetics, Kinesins genetics, Mice, Knockout, Mice, Transgenic, Renal Insufficiency genetics, Renal Insufficiency metabolism, Stromal Interaction Molecule 1 genetics, Urea blood, Urea urine, Urination drug effects, Water-Electrolyte Balance genetics, Kidney metabolism, Kinesins metabolism, Stromal Interaction Molecule 1 metabolism, Water metabolism
- Abstract
Background/aim: STIM1 is as an essential component in store operated Ca2+ entry. However give the paucity of information on the role of STIM1 in kidney, the aim was to study the function of STIM1 in the medulla of the kidney., Methods: we crossed a Ksp-cre mouse with another mouse containing two loxP sites flanking Exon 6 of STIM1. The Ksp-cre mouse is based upon the Ksp-cadherin gene promoter which expresses cre recombinase in developing nephrons, collecting ducts (SD) and thick ascending limbs (TAL) of the loop of Henle., Results: The offspring of these mice are viable without gross morphological changes, however, we noticed that the STIM1 Ksp-cre knockout mice produced more urine compared to control. To examine this more carefully, we fed mice low (LP) and high protein (HP) diets respectively. When mice were fed HP diet STIM1 ko mice had significantly increased urinary volume and lower specific gravity compared to wt mice. In STIM1 ko mice fed HP diet urine creatinine and urea were significantly lower compared to wt mice fed HP diet, however the fractional excretion was the same., Conclusion: These data support the idea that STIM1 ko mice have impaired urinary concentrating ability when challenged with HP diet is most likely caused by impaired Ca2+-dependent signal transduction through the vasopressin receptor cascade., (© 2016 The Author(s) Published by S. Karger AG, Basel.)
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- 2016
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39. Sarcoidosis in native and transplanted kidneys: incidence, pathologic findings, and clinical course.
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Bagnasco SM, Gottipati S, Kraus E, Alachkar N, Montgomery RA, Racusen LC, and Arend LJ
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- Adult, Biopsy, Female, Humans, Male, Middle Aged, Retrospective Studies, Kidney pathology, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic etiology, Kidney Failure, Chronic pathology, Kidney Transplantation, Nephritis, Interstitial epidemiology, Nephritis, Interstitial etiology, Nephritis, Interstitial pathology, Sarcoidosis epidemiology, Sarcoidosis etiology, Sarcoidosis pathology
- Abstract
Unlabelled: Renal involvement by sarcoidosis in native and transplanted kidneys classically presents as non caseating granulomatous interstitial nephritis. However, the incidence of sarcoidosis in native and transplant kidney biopsies, its frequency as a cause of end stage renal disease and its recurrence in renal allograft are not well defined, which prompted this study. The electronic medical records and the pathology findings in native and transplant kidney biopsies reviewed at the Johns Hopkins Hospital from 1/1/2000 to 6/30/2011 were searched. A total of 51 patients with a diagnosis of sarcoidosis and renal abnormalities requiring a native kidney biopsy were identified. Granulomatous interstitial nephritis, consistent with renal sarcoidosis was identified in kidney biopsies from 19 of these subjects (37%). This is equivalent to a frequency of 0.18% of this diagnosis in a total of 10,023 biopsies from native kidney reviewed at our institution. Follow-up information was available in 10 patients with biopsy-proven renal sarcoidosis: 6 responded to treatment with prednisone, one progressed to end stage renal disease. Renal sarcoidosis was the primary cause of end stage renal disease in only 2 out of 2,331 transplants performed. Only one biopsy-proven recurrence of sarcoidosis granulomatous interstitial nephritis was identified., Conclusions: Renal involvement by sarcoidosis in the form of granulomatous interstitial nephritis was a rare finding in biopsies from native kidneys reviewed at our center, and was found to be a rare cause of end stage renal disease. However, our observations indicate that recurrence of sarcoid granulomatous inflammation may occur in the transplanted kidney of patients with sarcoidosis as the original kidney disease.
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- 2014
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40. Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies.
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Gupta G, Abu Jawdeh BG, Racusen LC, Bhasin B, Arend LJ, Trollinger B, Kraus E, Rabb H, Zachary AA, Montgomery RA, and Alachkar N
- Subjects
- Adult, Allografts, Antibodies, Monoclonal, Murine-Derived therapeutic use, Baltimore, Biomarkers blood, Boronic Acids therapeutic use, Bortezomib, Creatinine blood, Drug Substitution, Female, Graft Rejection blood, Graft Rejection diagnosis, Graft Rejection immunology, Humans, Immunoglobulins, Intravenous therapeutic use, Immunosuppressive Agents adverse effects, Isoantibodies blood, Logistic Models, Male, Medication Adherence, Middle Aged, Multivariate Analysis, Odds Ratio, Pyrazines therapeutic use, Retrospective Studies, Risk Factors, Rituximab, Time Factors, Treatment Outcome, Graft Rejection therapy, Graft Survival, Immunity, Humoral, Immunosuppressive Agents therapeutic use, Kidney Transplantation adverse effects, Plasmapheresis
- Abstract
Background: Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR., Methods: Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength., Results: Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06)., Conclusions: A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.
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- 2014
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41. Histologic phenotype on 1-year posttransplantation biopsy and allograft survival in HLA-incompatible kidney transplants.
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Sharif A, Kraus ES, Zachary AA, Lonze BE, Nazarian SM, Segev DL, Alachkar N, Arend LJ, Bagnasco SM, Racusen LC, and Montgomery RA
- Subjects
- Adult, Allografts, Biopsy, Complement C4b metabolism, Female, Follow-Up Studies, Glomerulonephritis epidemiology, Glomerulonephritis metabolism, Glomerulonephritis pathology, Graft Rejection immunology, Humans, Kidney metabolism, Male, Middle Aged, Multivariate Analysis, Peptide Fragments metabolism, Prevalence, Prospective Studies, Retrospective Studies, Graft Rejection epidemiology, Graft Survival immunology, Histocompatibility immunology, Kidney pathology, Kidney Transplantation, Phenotype
- Abstract
Background: The correlation between histopathologic phenotypes and allograft outcomes among patients desensitized for donor-specific antibody (HLA-incompatible) is unknown., Methods: We analyzed 1-year biopsies from desensitized recipients transplanted between 1999 and 2010 and estimated graft survival for each histologic phenotype identified. Median time posttransplant for the 1-year biopsy was 367 days (interquartile range 357-388 days) and median follow-up of all patients post-1-year biopsy was 42 months (interquartile range 19.5-65 months)., Results: Transplant glomerulopathy was present in 25.0% of biopsies and resulted in worse graft survival (66.7% vs. 96.7%, P<0.001). C4d positivity and transplant glomerulopathy together portended exceptionally poor graft survival (33.3% vs. 97.2%, P<0.001). Microcirculation inflammation was prevalent, with glomerulitis and peritubular capillaritis found in 60.0% and 47.6% of 1-year biopsies, respectively. Glomerulitis was associated with worse graft survival (82.1% vs. 98.1%, P=0.004), whereas capillaritis was not (88.1% vs. 97.7% respectively, P=0.091). Among C4d-negative HLA-incompatible recipients (82.6% of biopsies), no difference in graft survival was observed between patients with or without microcirculation inflammation in contrast to previous reports by other investigators. Patients who had no C4d deposition, transplant glomerulopathy, or microcirculation inflammation had a 100.0% graft survival. On Cox regression analysis, no independent histopathological parameter was associated with graft survival., Conclusions: We have identified several histopathologic phenotypes in HLA-incompatible kidney recipients that correlate with allograft outcomes. Characterization of these phenotypes is the first step towards better understanding the pathophysiologic basis of chronic antibody-mediated allograft injury and individualizing therapeutic intervention.
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- 2014
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42. Novel roles of Pkd2 in male reproductive system development.
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Nie X and Arend LJ
- Subjects
- Animals, Epididymis cytology, Epididymis embryology, Epididymis metabolism, Epithelial Cells metabolism, Male, Mice, Protein Serine-Threonine Kinases genetics, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Testis cytology, Testis embryology, Wnt Signaling Pathway, Wolffian Ducts cytology, Wolffian Ducts embryology, Protein Serine-Threonine Kinases metabolism, Testis metabolism, Wolffian Ducts metabolism
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited genetic diseases, caused by mutations in PKD1 and/ or PKD2. Infertility and reproductive tract abnormalities in male ADPKD patients are very common and have higher incidence than in the general population. In this work, we reveal novel roles of Pkd2 for male reproductive system development. Disruption of Pkd2 caused dilation of mesonephric tubules/efferent ducts, failure of epididymal coiling, and defective testicular development. Deletion of Pkd2 in the epithelia alone was sufficient to cause reproductive tract defects seen in Pkd2(-/-) mice, suggesting that epithelial Pkd2 plays a pivotal role for development and maintenance of the male reproductive tract. In the testis, Pkd2 also plays a role in interstitial tissue and testicular cord development. In-depth analysis of epithelial-specific knockout mice revealed that Pkd2 is critical to maintain cellular phenotype and developmental signaling in the male reproductive system. Taken together, our data for the first time reveal novel roles for Pkd2 in male reproductive system development and provide new insights in male reproductive system abnormality and infertility in ADPKD patients., Competing Interests: Authors declare that there are no conflicts of interest., (Copyright © 2014 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)
- Published
- 2014
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43. Time course of pathologic changes in kidney allografts of positive crossmatch HLA-incompatible transplant recipients.
- Author
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Bagnasco SM, Zachary AA, Racusen LC, Arend LJ, Carter-Monroe N, Alachkar N, Nazarian SM, Lonze BE, Montgomery RA, and Kraus ES
- Subjects
- Adult, Aged, Antibodies chemistry, Biopsy, Complement C4b immunology, Disease Progression, Female, Follow-Up Studies, Graft Survival immunology, Histocompatibility Testing, Humans, Immunosuppression Therapy methods, Inflammation, Kidney pathology, Kidney Diseases immunology, Kidney Diseases therapy, Male, Microcirculation, Middle Aged, Peptide Fragments immunology, Risk Factors, Time Factors, Tissue Donors, Young Adult, HLA Antigens immunology, Kidney immunology, Kidney Transplantation adverse effects, Kidney Transplantation methods, Renal Insufficiency immunology
- Abstract
Background: Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression., Methods: We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years)., Results: Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg≥1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P<0.0001 and P<0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g≥1 and ptc≥1) with detectable donor-specific antibodies was observed in some recipients (<20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P<0.001)., Conclusions: Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.
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- 2014
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44. Pkd1 is required for male reproductive tract development.
- Author
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Nie X and Arend LJ
- Subjects
- Animals, Cytoskeleton metabolism, Cytoskeleton ultrastructure, Embryo, Mammalian, Epididymis abnormalities, Gene Expression Regulation, Developmental, Humans, Infertility, Male embryology, Infertility, Male metabolism, Infertility, Male pathology, Integrases genetics, Integrases metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, PAX2 Transcription Factor genetics, PAX2 Transcription Factor metabolism, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, Signal Transduction, TRPP Cation Channels deficiency, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Tubulin metabolism, Tubulin ultrastructure, Urothelium abnormalities, Wolffian Ducts abnormalities, Body Patterning genetics, Epididymis metabolism, Infertility, Male genetics, TRPP Cation Channels genetics, Urothelium metabolism, Wolffian Ducts metabolism
- Abstract
Reproductive tract abnormalities and male infertility have higher incidence in ADPKD patients than in general populations. In this work, we reveal that Pkd1, whose mutations account for 85% of ADPKD cases, is essential for male reproductive tract development. Disruption of Pkd1 caused multiple organ defects in the murine male reproductive tract. The earliest visible defect in the Pkd1(-/-) reproductive tract was cystic dilation of the efferent ducts, which are derivatives of the mesonephric tubules. Epididymis development was delayed or arrested in the Pkd1(-/-) mice. No sign of epithelial coiling was seen in the null mutants. Disruption of Pkd1 in epithelium alone using the Pax2-cre mice was sufficient to cause efferent duct dilation and coiling defect in the epididymis, suggesting that Pkd1 is critical for epithelium development and maintenance in male reproductive tract. In-depth analysis showed that Pkd1 is required to maintain tubulin cytoskeleton and important for Tgf-β/Bmp signal transduction in epithelium of male reproductive tract. Altogether, our results for the first time provide direct evidence for developmental roles of Pkd1 in the male reproductive tract and provide new insights in reproductive tract abnormalities and infertility in ADPKD patients., Competing Interests: Authors declare that there are no conflicts of interest., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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45. Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy.
- Author
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Alachkar N, Wei C, Arend LJ, Jackson AM, Racusen LC, Fornoni A, Burke G, Rabb H, Kakkad K, Reiser J, and Estrella MM
- Subjects
- Adult, Antibodies, Monoclonal, Murine-Derived therapeutic use, Biomarkers blood, Biopsy, C-Reactive Protein metabolism, Female, Glomerular Filtration Rate, Glomerulosclerosis, Focal Segmental blood, Glomerulosclerosis, Focal Segmental pathology, Glomerulosclerosis, Focal Segmental physiopathology, Humans, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Plasmapheresis, Podocytes drug effects, Proteinuria blood, Proteinuria pathology, Proteinuria therapy, Recurrence, Retrospective Studies, Rituximab, Time Factors, Treatment Outcome, Young Adult, Glomerulosclerosis, Focal Segmental surgery, Kidney Transplantation adverse effects, Podocytes pathology, Receptors, Urokinase Plasminogen Activator blood
- Abstract
Background: Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30% of cases and can lead to allograft loss. Serum soluble urokinase-type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS., Methods: We conducted a retrospective study of 25 adults with posttransplantation FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function, and resolution of histologic changes., Results: A median (interquartile range) of 15 (10-23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pretreatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4806 pg/mL; P=0.02). Overall, mean±SD of proteinuria improved from 5.1±3.8 to 2.1±2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57%±33% to 22%±22% (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6-44.2) to 39.3 (28.8-63.4; P<0.0001), and suPAR levels decreased from a median of 6.781 to 4.129 pg/mL (P=0.02) with therapy., Conclusions: Podocyte effacement is the first pathologic manifestation of FSGS after transplantation. The degree of podocyte effacement correlates with suPAR levels at time of diagnosis. Response to therapy results in significant reduction of suPAR levels and complete or significant improvement of podocyte effacement.
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- 2013
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46. Deletion of the pH sensor GPR4 decreases renal acid excretion.
- Author
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Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, and Petrovic S
- Subjects
- Acidosis, Renal Tubular metabolism, Acids metabolism, Animals, Cell Line, Cyclic AMP metabolism, Humans, Hydrogen-Ion Concentration, Mice, Mice, Knockout, RNA, Messenger metabolism, Receptors, G-Protein-Coupled genetics, Acid-Base Equilibrium, Kidney Tubules, Collecting metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
Proton receptors are G protein-coupled receptors that accept protons as ligands and function as pH sensors. One of the proton receptors, GPR4, is relatively abundant in the kidney, but its potential role in acid-base homeostasis is unknown. In this study, we examined the distribution of GPR4 in the kidney, its function in kidney epithelial cells, and the effects of its deletion on acid-base homeostasis. We observed GPR4 expression in the kidney cortex, in the outer and inner medulla, in isolated kidney collecting ducts, and in cultured outer and inner medullary collecting duct cells (mOMCD1 and mIMCD3). Cultured mOMCD1 cells exhibited pH-dependent accumulation of intracellular cAMP, characteristic of GPR4 activation; GPR4 knockdown attenuated this accumulation. In vivo, deletion of GPR4 decreased net acid secretion by the kidney and resulted in a nongap metabolic acidosis, indicating that GPR4 is required to maintain acid-base homeostasis. Collectively, these findings suggest that GPR4 is a pH sensor with an important role in regulating acid secretion in the kidney collecting duct.
- Published
- 2010
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47. Proteasome inhibitor-based primary therapy for antibody-mediated renal allograft rejection.
- Author
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Walsh RC, Everly JJ, Brailey P, Rike AH, Arend LJ, Mogilishetty G, Govil A, Roy-Chaudhury P, Alloway RR, and Woodle ES
- Subjects
- Adult, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Murine-Derived, Biopsy, Bortezomib, Creatinine blood, Female, Humans, Immunologic Factors therapeutic use, Immunosuppression Therapy methods, Isoantibodies immunology, Kidney Failure, Chronic surgery, Kidney Transplantation immunology, Rituximab, Transplantation, Homologous pathology, Young Adult, Boronic Acids therapeutic use, Graft Rejection drug therapy, Graft Rejection prevention & control, HLA Antigens immunology, Kidney Transplantation pathology, Protease Inhibitors therapeutic use, Pyrazines therapeutic use
- Abstract
Background: Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented., Methods: Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m2) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform., Results: Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination., Conclusions: Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.
- Published
- 2010
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48. Deletion of the chloride transporter slc26a7 causes distal renal tubular acidosis and impairs gastric acid secretion.
- Author
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Xu J, Song P, Nakamura S, Miller M, Barone S, Alper SL, Riederer B, Bonhagen J, Arend LJ, Amlal H, Seidler U, and Soleimani M
- Subjects
- Acidosis, Renal Tubular genetics, Animals, Humans, Hydrogen-Ion Concentration, Mice, Mice, Knockout, Mice, Mutant Strains, Sulfate Transporters, Acidosis, Renal Tubular metabolism, Chloride-Bicarbonate Antiporters, Gastric Acid metabolism, Gastric Mucosa metabolism, Kidney Medulla metabolism
- Abstract
SLC26A7 (human)/Slc26a7 (mouse) is a recently identified chloride-base exchanger and/or chloride transporter that is expressed on the basolateral membrane of acid-secreting cells in the renal outer medullary collecting duct (OMCD) and in gastric parietal cells. Here, we show that mice with genetic deletion of Slc26a7 expression develop distal renal tubular acidosis, as manifested by metabolic acidosis and alkaline urine pH. In the kidney, basolateral Cl(-)/HCO3(-) exchange activity in acid-secreting intercalated cells in the OMCD was significantly decreased in hypertonic medium (a normal milieu for the medulla) but was reduced only mildly in isotonic medium. Changing from a hypertonic to isotonic medium (relative hypotonicity) decreased the membrane abundance of Slc26a7 in kidney cells in vivo and in vitro. In the stomach, stimulated acid secretion was significantly impaired in isolated gastric mucosa and in the intact organ. We propose that SLC26A7 dysfunction should be investigated as a potential cause of unexplained distal renal tubular acidosis or decreased gastric acid secretion in humans.
- Published
- 2009
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49. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.
- Author
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Everly MJ, Everly JJ, Arend LJ, Brailey P, Susskind B, Govil A, Rike A, Roy-Chaudhury P, Mogilishetty G, Alloway RR, Tevar A, and Woodle ES
- Subjects
- Adult, Autoantibodies blood, Biopsy, Black People, Delayed Graft Function epidemiology, Female, Graft Rejection blood, HLA Antigens immunology, Humans, Kidney Transplantation immunology, Kidney Transplantation pathology, Male, Middle Aged, Multivariate Analysis, Regression Analysis, Renal Replacement Therapy, Risk Factors, Transplantation, Homologous immunology, Transplantation, Homologous physiology, Treatment Failure, Black or African American, Graft Rejection immunology, Graft Survival immunology, Isoantibodies blood, Isoantibodies immunology, Kidney Transplantation physiology
- Abstract
The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 +/- 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody-mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.
- Published
- 2009
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50. Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice.
- Author
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Zahedi K, Lentsch AB, Okaya T, Barone S, Sakai N, Witte DP, Arend LJ, Alhonen L, Jell J, Jänne J, Porter CW, and Soleimani M
- Subjects
- Acetyltransferases metabolism, Animals, Kidney metabolism, Kidney pathology, Kidney Diseases enzymology, Liver metabolism, Liver pathology, Liver Diseases enzymology, Mice, Mice, Knockout, Polyamines metabolism, Acetyltransferases genetics, Kidney Diseases pathology, Liver Diseases pathology, Reperfusion Injury metabolism
- Abstract
Expression of spermine/spermidine-N1-acetyltransferase (SSAT), the rate-limiting enzyme of polyamine backconversion cascade, increases after ischemia-reperfusion injuries (IRI). We hypothesized that SSAT plays an important role in the mediation of IRI. To test our hypothesis, wild-type (SSAT-wt) and SSAT-deficient (SSAT-ko) mice were subjected to liver or kidney IRI by ligation of hepatic or renal arteries. The liver and kidney content of putrescine (Put), a downstream by-product of SSAT activity, increased in SSAT-wt animals but not in SSAT-ko animals after IRI, indicating that polyamine backconversion is not functional in SSAT-deficient mice. When subjected to hepatic IRI, SSAT-ko mice were significantly protected against liver damage compared with SSAT-wt mice. Similarly, SSAT-ko animals subjected to renal IRI showed significantly greater protection against damage to kidney tubules than SSAT-wt mice. These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI.
- Published
- 2009
- Full Text
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