Publications by authors named "Agnes B Fogo"

357 Publications

Do Proton-Pump Inhibitors Cause CKD and Progression of CKD?: COMMENTARY.

Kidney360 2022 07 4;3(7):1141-1143. Epub 2022 Jan 4.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

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http://dx.doi.org/10.34067/KID.0008302021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337904PMC
July 2022

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model.

Kidney360 2022 07 18;3(7):1169-1182. Epub 2022 Apr 18.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril.

Methods: Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses.

Results: All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing.

Conclusions: Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.
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http://dx.doi.org/10.34067/KID.0001032022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337896PMC
July 2022

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis.

Clin J Am Soc Nephrol 2022 Jul;17(7):994-1007

Department for Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom

Background And Objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years.

Design, Setting, Participants, & Measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome.

Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores.

Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.
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http://dx.doi.org/10.2215/CJN.16801221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269630PMC
July 2022

Glo-In-One: holistic glomerular detection, segmentation, and lesion characterization with large-scale web image mining.

J Med Imaging (Bellingham) 2022 Sep 20;9(5):052408. Epub 2022 Jun 20.

Vanderbilt University, Department of Computer Science, Nashville, Tennessee, United States.

The quantitative detection, segmentation, and characterization of glomeruli from high-resolution whole slide imaging (WSI) play essential roles in the computer-assisted diagnosis and scientific research in digital renal pathology. Historically, such comprehensive quantification requires extensive programming skills to be able to handle heterogeneous and customized computational tools. To bridge the gap of performing glomerular quantification for non-technical users, we develop the Glo-In-One toolkit to achieve holistic glomerular detection, segmentation, and characterization via a single line of command. Additionally, we release a large-scale collection of 30,000 unlabeled glomerular images to further facilitate the algorithmic development of self-supervised deep learning. The inputs of the Glo-In-One toolkit are WSIs, while the outputs are (1) WSI-level multi-class circle glomerular detection results (which can be directly manipulated with ImageScope), (2) glomerular image patches with segmentation masks, and (3) different lesion types. In the current version, the fine-grained global glomerulosclerosis (GGS) characterization is provided, including assessed-solidified-GSS (associated with hypertension-related injury), disappearing-GSS (a further end result of the SGGS becoming contiguous with fibrotic interstitium), and obsolescent-GSS (nonspecific GGS increasing with aging) glomeruli. To leverage the performance of the Glo-In-One toolkit, we introduce self-supervised deep learning to glomerular quantification via large-scale web image mining. The GGS fine-grained classification model achieved a decent performance compared with baseline supervised methods while only using 10% of the annotated data. The glomerular detection achieved an average precision of 0.627 with circle representations, while the glomerular segmentation achieved a 0.955 patch-wise Dice dimilarity coefficient. We develop and release an open-source Glo-In-One toolkit, a software with holistic glomerular detection, segmentation, and lesion characterization. This toolkit is user-friendly to non-technical users via a single line of command. The toolbox and the 30,000 web mined glomerular images have been made publicly available at https://github.com/hrlblab/Glo-In-One.
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http://dx.doi.org/10.1117/1.JMI.9.5.052408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207519PMC
September 2022

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease.

JCI Insight 2022 06 22;7(12). Epub 2022 Jun 22.

Division of Nephrology and Hypertension, Department of Medicine, Washington University St. Louis, St. Louis, Missouri, USA.

Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression quantitative trait loci (eQTLs) for CCND1 (cyclin D1) and the CDK4/6 inhibitor CDKN2B were associated with eGFR in genome-wide association studies. Consistent with the preclinical studies, reduced expression of CDKN2B correlated with lower eGFR values, and higher levels of CCND1 correlated with higher eGFR values. CDK4/6 inhibition promoted tubular cell survival, in part, through a STAT3/IL-1β pathway and was dependent upon on its effects on the cell cycle. Our data challenge the paradigm that tubular cell cycle progression is beneficial in the context of chronic kidney injury. Unlike the reparative role of cell cycle progression following acute kidney injury, these data suggest that blocking cell cycle progression by inhibiting CDK4/6, but not cyclin D1, protects against chronic kidney injury.
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http://dx.doi.org/10.1172/jci.insight.158754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309053PMC
June 2022

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

Int J Mol Sci 2022 May 27;23(11). Epub 2022 May 27.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.
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http://dx.doi.org/10.3390/ijms23116018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181646PMC
May 2022

Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus.

JCI Insight 2022 07 8;7(13). Epub 2022 Jul 8.

Division of Clinical Pharmacology and.

We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
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http://dx.doi.org/10.1172/jci.insight.136678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310530PMC
July 2022

Multi-contrast computed tomography healthy kidney atlas.

Comput Biol Med 2022 07 26;146:105555. Epub 2022 Apr 26.

Vanderbilt University, Department of Computer Science, Nashville, USA; Vanderbilt University Medical Center, Department of Radiology, Nashville, USA.

The construction of three-dimensional multi-modal tissue maps provides an opportunity to spur interdisciplinary innovations across temporal and spatial scales through information integration. While the preponderance of effort is allocated to the cellular level and explore the changes in cell interactions and organizations, contextualizing findings within organs and systems is essential to visualize and interpret higher resolution linkage across scales. There is a substantial normal variation of kidney morphometry and appearance across body size, sex, and imaging protocols in abdominal computed tomography (CT). A volumetric atlas framework is needed to integrate and visualize the variability across scales. However, there is no abdominal and retroperitoneal organs atlas framework for multi-contrast CT. Hence, we proposed a high-resolution CT retroperitoneal atlas specifically optimized for the kidney organ across non-contrast CT and early arterial, late arterial, venous and delayed contrast-enhanced CT. We introduce a deep learning-based volume interest extraction method by localizing the 2D slices with a representative score and crop within the range of the abdominal interest. An automated two-stage hierarchal registration pipeline is then performed to register abdominal volumes to a high-resolution CT atlas template with DEEDS affine and non-rigid registration. To generate and evaluate the atlas framework, multi-contrast modality CT scans of 500 subjects (without reported history of renal disease, age: 15-50 years, 250 males & 250 females) were processed. PDD-Net with affine registration achieved the best overall mean DICE for portal venous phase multi-organs label transfer with the registration pipeline (0.540 ± 0.275, p < 0.0001 Wilcoxon signed-rank test) comparing to the other registration tools. It also demonstrated the best performance with the median DICE over 0.8 in transferring the kidney information to the atlas space. DEEDS perform constantly with stable transferring performance in all phases average mapping including significant clear boundary of kidneys with contrastive characteristics, while PDD-Net only demonstrates a stable kidney registration in the average mapping of early and late arterial, and portal venous phase. The variance mappings demonstrate the low intensity variance in the kidney regions with DEEDS across all contrast phases and with PDD-Net across late arterial and portal venous phase. We demonstrate a stable generalizability of the atlas template for integrating the normal kidney variation from small to large, across contrast modalities and populations with great variability of demographics. The linkage of atlas and demographics provided a better understanding of the variation of kidney anatomy across populations.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105555DOI Listing
July 2022

The role of mineralocorticoid receptor activation in kidney inflammation and fibrosis.

Kidney Int Suppl (2011) 2022 Apr 18;12(1):63-68. Epub 2022 Mar 18.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Chronic kidney disease is characterized by progressive scarring that results in loss of normal tissue in the kidney and eventually end-stage kidney disease. Interstitial fibrosis and tubular atrophy have been most closely correlated with decline in renal function. Potential mechanisms include profibrotic changes in tubules, influx of profibrotic rather than healing reparative macrophages, and an increase in activated myofibroblasts. Aldosterone activates the mineralocorticoid receptor in the collecting duct to increase sodium reabsorption, resulting in increased blood pressure. Aldosterone also promotes inflammation and fibrosis in the kidney by activating the mineralocorticoid receptor in other cellular compartments, including podocytes, mesangial cells, epithelial cells, and myeloid cells. Aldosterone also may act indirectly by stimulating factors in epithelial tissues that contribute to inflammatory macrophage polarization, myofibroblast differentiation, and progressive fibrosis. This review discusses the potential mechanisms by which aldosterone and mineralocorticoid receptor activation promotes inflammation and fibrosis via nonclassical pathways in the kidney.
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http://dx.doi.org/10.1016/j.kisu.2021.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9073221PMC
April 2022

Quantitative super-resolution microscopy reveals promoting mitochondrial interconnectivity protects against AKI.

Kidney360 2021 12 30;2(12):1892-1907. Epub 2021 Dec 30.

Division of Nephrology and Hypertension, School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA.

Background: The root of many kidney diseases in humans can be traced to alterations or damage to subcellular organelles. Mitochondrial fragmentation, endoplasmic reticulum (ER) stress, and lysosomal inhibition, among others, ultimately contribute to kidney injury and are the target of therapeutics in development. Although recent technological advancements allow for the understanding of disease states at the cellular level, investigating changes in subcellular organelles from kidney tissue remains challenging.

Methods: Using structured illumination microscopy, we imaged mitochondria and other organelles from paraffin sections of mouse tissue and human kidney biopsy specimens. The resulting images were 3D rendered to quantify mitochondrial size, content, and morphology. Results were compared with those from transmission electron microscopy and segmentation.

Results: Super-resolution imaging reveals kidney tubular epithelial cell mitochondria in rodent and human kidney tissue form large, interconnected networks under basal conditions, which are fragmented with injury. This approach can be expanded to other organelles and cellular structures including autophagosomes, ER, brush border, and cell morphology. We find that, during unilateral ischemia, mitochondrial fragmentation occurs in most tubule cells, and they remain fragmented for >96 hours. Promoting mitochondrial fusion with the fusion promotor M1 preserves mitochondrial morphology and interconnectivity and protects against cisplatin-induced kidney injury.

Conclusions: We provide, for the first time, a nonbiased, semiautomated approach for quantification of the 3D morphology of mitochondria in kidney tissue. Maintaining mitochondrial interconnectivity and morphology protects against kidney injury. Super-resolution imaging has the potential to both drive discovery of novel pathobiologic mechanisms in kidney tissue and broaden the diagnoses that can be made on human biopsy specimens.
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http://dx.doi.org/10.34067/kid.0001602021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953106PMC
December 2021

Holistic fine-grained global glomerulosclerosis characterization: from detection to unbalanced classification.

J Med Imaging (Bellingham) 2022 Jan 17;9(1):014005. Epub 2022 Feb 17.

Vanderbilt University, Department of Electrical Engineering and Computer Science, Nashville, United States.

Recent studies have demonstrated the diagnostic and prognostic values of global glomerulosclerosis (GGS) in IgA nephropathy, aging, and end-stage renal disease. However, the fine-grained quantitative analysis of multiple GGS subtypes (e.g., obsolescent, solidified, and disappearing glomerulosclerosis) is typically a resource extensive manual process. Very few automatic methods, if any, have been developed to bridge this gap for such analytics. We present a holistic pipeline to quantify GGS (with both detection and classification) from a whole slide image in a fully automatic manner. In addition, we conduct the fine-grained classification for the subtypes of GGS. Our study releases the open-source quantitative analytical tool for fine-grained GGS characterization while tackling the technical challenges in unbalanced classification and integrating detection and classification. We present a deep learning-based framework to perform fine-grained detection and classification of GGS, with a hierarchical two-stage design. Moreover, we incorporate the state-of-the-art transfer learning techniques to achieve a more generalizable deep learning model for tackling the imbalanced distribution of our dataset. This way, we build a highly efficient WSI-to-results GGS characterization pipeline. Meanwhile, we investigated the largest fine-grained GGS cohort as of yet with 11,462 glomeruli and 10,619 nonglomeruli, which include 7841 globally sclerotic glomeruli of three distinct categories. With these data, we apply deep learning techniques to achieve (1) fine-grained GGS characterization, (2) GGS versus non-GGS classification, and (3) improved glomeruli detection results. For fine-grained GGS characterization, when pretrained on the larger dataset, our model can achieve a 0.778-macro- score, compared to a 0.746-macro- score when using the regular ImageNet-pretrained weights. On the external dataset, our best model achieves an area under the curve (AUC) score of 0.994 when tasked with differentiating GGS from normal glomeruli. Using our dataset, we are able to build algorithms that allow for fine-grained classification of glomeruli lesions and are robust to distribution shifts. Our study showed that the proposed methods consistently improve the detection and fine-grained classification performance through both cross validation and external validation. Our code and pretrained models have been released for public use at https://github.com/luyuzhe111/glomeruli.
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http://dx.doi.org/10.1117/1.JMI.9.1.014005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853712PMC
January 2022

Approach to Kidney Biopsy: Core Curriculum 2022.

Am J Kidney Dis 2022 07 4;80(1):119-131. Epub 2022 Feb 4.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

The kidney biopsy is an essential tool for diagnosis of many kidney diseases. Obtaining an adequate biopsy sample with appropriate allocation for various studies is essential. Nephrologists should understand key lesions and their interpretation because these are essential elements underlying optimal approaches for interventions. This installment in the AJKD Core Curriculum in Nephrology will review these topics. We will first briefly discuss considerations for allocation and processing of kidney biopsies. We will then present in outline form the differential diagnoses of a spectrum of patterns of injury and consideration for interpretation of specific lesions. Lesions are presented according to anatomic site as glomerular, vascular, or tubulointerstitial. Native and transplant kidney biopsy lesions are included. These lesions and differential diagnoses and specific diseases are then linked to detailed clinicopathologic discussion of specific diseases presented in the AJKD Atlas of Kidney Pathology II. Correlation with immunofluorescence, electron microscopy, and clinical findings are emphasized to reach a differential diagnosis and the final diagnosis.
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http://dx.doi.org/10.1053/j.ajkd.2021.08.024DOI Listing
July 2022

Lipopolysaccharide Pretreatment Prevents Medullary Vascular Congestion following Renal Ischemia by Limiting Early Reperfusion of the Medullary Circulation.

J Am Soc Nephrol 2022 04 3;33(4):769-785. Epub 2022 Feb 3.

Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia

Background: Vascular congestion of the renal medulla-trapped red blood cells in the medullary microvasculature-is a hallmark finding at autopsy in patients with ischemic acute tubular necrosis. Despite this, the pathogenesis of vascular congestion is not well defined.

Methods: In this study, to investigate the pathogenesis of vascular congestion and its role in promoting renal injury, we assessed renal vascular congestion and tubular injury after ischemia reperfusion in rats pretreated with low-dose LPS or saline (control). We used laser Doppler flowmetry to determine whether pretreatment with low-dose LPS prevented vascular congestion by altering renal hemodynamics during reperfusion.

Results: We found that vascular congestion originated during the ischemic period in the renal venous circulation. In control animals, the return of blood flow was followed by the development of congestion in the capillary plexus of the outer medulla and severe tubular injury early in reperfusion. Laser Doppler flowmetry indicated that blood flow returned rapidly to the medulla, several minutes before recovery of full cortical perfusion. In contrast, LPS pretreatment prevented both the formation of medullary congestion and its associated tubular injury. Laser Doppler flowmetry in LPS-pretreated rats suggested that limiting early reperfusion of the medulla facilitated this protective effect, because it allowed cortical perfusion to recover and clear congestion from the large cortical veins, which also drain the medulla.

Conclusions: Blockage of the renal venous vessels and a mismatch in the timing of cortical and medullary reperfusion results in congestion of the outer medulla's capillary plexus and promotes early tubular injury after renal ischemia. These findings indicate that hemodynamics during reperfusion contribute to the renal medulla's susceptibility to ischemic injury.
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http://dx.doi.org/10.1681/ASN.2021081089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970460PMC
April 2022

De Novo Immunoglobulin A Vasculitis Following Exposure to SARS-CoV-2 Immunization.

Ochsner J 2021 ;21(4):395-401

Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA.

Immunizations have been previously described as potential triggering events for the development of certain glomerular diseases. However, glomerular disease occurrences are being reported after exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. A 50-year-old male presented to a nephrology clinic for evaluation of persistent proteinuria. Six weeks prior to evaluation, the patient had reported developing a rash 2 weeks after receiving the first dose of a SARS-CoV-2 vaccine (BNT162b2 mRNA, Pfizer, Inc). His primary care provider treated the rash with corticosteroids, leading to partial improvement of the skin lesions. Three weeks after the first vaccine injection, the patient received his scheduled second vaccine injection. Within 2 days, the rash reappeared. This time, the lesions were more severe in nature. Skin biopsy revealed immunoglobulin A (IgA)-dominant leukocytoclastic vasculitis. After the patient completed 2 weeks of oral corticosteroids, urinalysis revealed proteinuria, and consultation with nephrology was requested. On examination, healing papules were noted on his legs. Serum creatinine 2 weeks after the second dose of vaccine was 0.9 mg/dL. Microscopic examination of the urinary sediment revealed acanthocytes. Urine protein to creatinine ratio 3 weeks after the second dose of vaccine was 1.1 g/day. Serum complements were normal, and all pertinent serology was negative. Kidney biopsy findings were consistent with IgA nephropathy. The clinical presentation and pathologic findings in this case strongly suggest that the Pfizer SARS-CoV-2 vaccine can trigger a clinical syndrome compatible with Henoch-Schönlein purpura. The recurrence of the rash following the second dose argues for a definite causal association by the Naranjo criteria.
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http://dx.doi.org/10.31486/toj.21.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675622PMC
January 2021

Cell-Mediated Glomerulonephritis Without Immune Complexes in Native Kidney Biopsies: A Report of 7 Cases.

Am J Kidney Dis 2021 Dec 30. Epub 2021 Dec 30.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:

We report 7 native kidney biopsies with diffuse endocapillary hypercellularity without immune deposits, affecting 5 women and 2 men aged 52-85 years. All patients had acute kidney injury, and 4 had nephrotic-range proteinuria. Comorbidities included breast cancer in 2, pancreatitis in 1, and para-aortic lymphadenopathy and bilateral carpal tunnel syndrome in 1. Kidney biopsies were characterized by predominant T-cell and CD68-positive macrophage infiltration in glomerular capillaries without deposits. Coexisting lesions included small cellular crescents in 5, mild peritubular capillaritis in 1, mononuclear cell intimal arteritis in 1, acute tubulointerstitial nephritis in 4, and mild arteriolosclerosis in 1. During the mean follow-up duration of 24.8 months, 4 patients showed partial or complete initial remission in response to immunosuppression. However, 2 deteriorated when prednisone was rapidly tapered (1 of them achieved subsequent remission with increased prednisone). Three patients developed kidney failure. We propose that this unusual pattern of injury is mediated by abnormal cell-mediated immune response. The underlying causes and pathogenesis of this cell-mediated glomerulonephritis will require further study.
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http://dx.doi.org/10.1053/j.ajkd.2021.11.009DOI Listing
December 2021

DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3.

JCI Insight 2022 02 8;7(3). Epub 2022 Feb 8.

Department of Medicine, Division of Nephrology and Hypertension, and.

Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal tubule epithelial cells. DDR1-induced BCR phosphorylation or BCR downregulation increased MCP-1 secretion, suggesting that BCR negatively regulates the levels of MCP-1. Mechanistically, phosphorylation or downregulation of BCR increased β-catenin activity and in turn MCP-1 production. Finally, we showed that DDR1-mediated STAT3 activation was required to stimulate the secretion of TGF-β. Thus, DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-β. These findings identify DDR1 an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease.
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http://dx.doi.org/10.1172/jci.insight.150887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855801PMC
February 2022

The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis.

Kidney Int 2022 01 9;101(1):152-163. Epub 2021 Nov 9.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region.
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http://dx.doi.org/10.1016/j.kint.2021.10.019DOI Listing
January 2022

Circle Representation for Medical Object Detection.

IEEE Trans Med Imaging 2022 03 2;41(3):746-754. Epub 2022 Mar 2.

Box representation has been extensively used for object detection in computer vision. Such representation is efficacious but not necessarily optimized for biomedical objects (e.g., glomeruli), which play an essential role in renal pathology. In this paper, we propose a simple circle representation for medical object detection and introduce CircleNet, an anchor-free detection framework. Compared with the conventional bounding box representation, the proposed bounding circle representation innovates in three-fold: (1) it is optimized for ball-shaped biomedical objects; (2) The circle representation reduced the degree of freedom compared with box representation; (3) It is naturally more rotation invariant. When detecting glomeruli and nuclei on pathological images, the proposed circle representation achieved superior detection performance and be more rotation-invariant, compared with the bounding box. The code has been made publicly available: https://github.com/hrlblab/CircleNet.
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http://dx.doi.org/10.1109/TMI.2021.3122835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963364PMC
March 2022

Gains in understanding of podocyte loss.

Authors:
Agnes B Fogo

Kidney Int 2021 11;100(5):978-980

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

Podocyte loss is a key element underlying glomerulosclerosis. Various mechanisms have been proposed for cell loss. These include local hemodynamic effects and local stresses on cell and hemodynamic changes, which together may contribute to detachment of podocytes, leading to sclerosis. Elegant studies based on classic observations add state-of-the-art imaging, modeling, intravital microscopy, and ultrastructural geometry analyses and provide new insights into potential mechanisms for injury and loss of this key cell.
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http://dx.doi.org/10.1016/j.kint.2021.08.003DOI Listing
November 2021

Rac1 promotes kidney collecting duct integrity by limiting actomyosin activity.

J Cell Biol 2021 11 14;220(11). Epub 2021 Oct 14.

Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

A polarized collecting duct (CD), formed from the branching ureteric bud (UB), is a prerequisite for an intact kidney. The small Rho GTPase Rac1 is critical for actin cytoskeletal regulation. We investigated the role of Rac1 in the kidney collecting system by selectively deleting it in mice at the initiation of UB development. The mice exhibited only a mild developmental phenotype; however, with aging, the CD developed a disruption of epithelial integrity and function. Despite intact integrin signaling, Rac1-null CD cells had profound adhesion and polarity abnormalities that were independent of the major downstream Rac1 effector, Pak1. These cells did however have a defect in the WAVE2-Arp2/3 actin nucleation and polymerization apparatus, resulting in actomyosin hyperactivity. The epithelial defects were reversible with direct myosin II inhibition. Furthermore, Rac1 controlled lateral membrane height and overall epithelial morphology by maintaining lateral F-actin and restricting actomyosin. Thus, Rac1 promotes CD epithelial integrity and morphology by restricting actomyosin via Arp2/3-dependent cytoskeletal branching.
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http://dx.doi.org/10.1083/jcb.202103080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563289PMC
November 2021

Highly multiplexed immunofluorescence of the human kidney using co-detection by indexing.

Kidney Int 2022 01 5;101(1):137-143. Epub 2021 Oct 5.

Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Electronic address:

The human kidney is composed of many cell types that vary in their abundance and distribution from normal to diseased organ. As these cell types perform unique and essential functions, it is important to confidently label each within a single tissue to accurately assess tissue architecture and microenvironments. Towards this goal, we demonstrate the use of co-detection by indexing (CODEX) multiplexed immunofluorescence for visualizing 23 antigens within the human kidney. Using CODEX, many of the major cell types and substructures, such as collecting ducts, glomeruli, and thick ascending limb, were visualized within a single tissue section. Of these antibodies, 19 were conjugated in-house, demonstrating the flexibility and utility of this approach for studying the human kidney using custom and commercially available antibodies. We performed a pilot study that compared both fresh frozen and formalin-fixed paraffin-embedded healthy non-neoplastic and diabetic nephropathy kidney tissues. The largest cellular differences between the two groups was observed in cells labeled with aquaporin 1, cytokeratin 7, and α-smooth muscle actin. Thus, our data show the power of CODEX multiplexed immunofluorescence for surveying the cellular diversity of the human kidney and the potential for applications within pathology, histology, and building anatomical atlases.
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http://dx.doi.org/10.1016/j.kint.2021.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741652PMC
January 2022

Renal Cortex, Medulla and Pelvicaliceal System Segmentation on Arterial Phase CT Images with Random Patch-based Networks.

Proc SPIE Int Soc Opt Eng 2021 15;11596. Epub 2021 Feb 15.

Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA 37212.

Renal segmentation on contrast-enhanced computed tomography (CT) provides distinct spatial context and morphology. Current studies for renal segmentations are highly dependent on manual efforts, which are time-consuming and tedious. Hence, developing an automatic framework for the segmentation of renal cortex, medulla and pelvicalyceal system is an important quantitative assessment of renal morphometry. Recent innovations in deep methods have driven performance toward levels for which clinical translation is appealing. However, the segmentation of renal structures can be challenging due to the limited field-of-view (FOV) and variability among patients. In this paper, we propose a method to automatically label the renal cortex, the medulla and pelvicalyceal system. First, we retrieved 45 clinically-acquired deidentified arterial phase CT scans (45 patients, 90 kidneys) without diagnosis codes (ICD-9) involving kidney abnormalities. Second, an interpreter performed manual segmentation to pelvis, medulla and cortex slice-by-slice on all retrieved subjects under expert supervision. Finally, we proposed a patch-based deep neural networks to automatically segment renal structures. Compared to the automatic baseline algorithm (3D U-Net) and conventional hierarchical method (3D U-Net Hierarchy), our proposed method achieves improvement of 0.7968 to 0.6749 (3D U-Net), 0.7482 (3D U-Net Hierarchy) in terms of mean Dice scores across three classes ( < 0.001, paired t-tests between our method and 3D U-Net Hierarchy). In summary, the proposed algorithm provides a precise and efficient method for labeling renal structures.
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http://dx.doi.org/10.1117/12.2581101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442958PMC
February 2021

IgA-dominant infection-associated glomerulonephritis in the pediatric population.

Pediatr Nephrol 2022 03 28;37(3):593-600. Epub 2021 Aug 28.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: IgA-dominant infection-associated glomerulonephritis is well-documented in adults but has not been studied in depth in children. We assessed the incidence of pediatric IgA-dominant infection-associated glomerulonephritis and clinical and kidney biopsy findings.

Methods: Pediatric native kidney biopsies over a 10-year period with IgA dominance, strong C3, and findings indicative of infection-associated etiology were identified.

Results: We identified 9 cases of IgA-dominant infection-associated glomerulonephritis, 0.8% of pediatric native kidney biopsies. Seven patients presented with elevated creatinine. All had hematuria and proteinuria. Eight patients had clinical evidence of infection: one each with central port infection by methicillin-sensitive Staphylococcus aureus, recurrent streptococcal pharyngitis and recent otitis media, streptococcal pharyngitis demonstrated 8 months after biopsy, suspected streptococcal scalded skin syndrome, and viral gastroenteritis, and three with serologic evidence of Streptococcal infection but no identified site of infection. All but one patient experienced short-term normalization of creatinine and resolution of proteinuria, though two eventually progressed to kidney failure: one 3 years later due to progressive disease and one 11 years later due to focal segmental glomerulosclerosis without concurrent immune deposits.

Conclusions: Pediatric IgA-dominant infection-associated glomerulonephritis is rare, and generally has a favorable prognosis, contrasting that seen in adults with severe comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary.
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http://dx.doi.org/10.1007/s00467-021-05245-yDOI Listing
March 2022

Protocol for multimodal analysis of human kidney tissue by imaging mass spectrometry and CODEX multiplexed immunofluorescence.

STAR Protoc 2021 09 13;2(3):100747. Epub 2021 Aug 13.

Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.

Here, we describe the preservation and preparation of human kidney tissue for interrogation by histopathology, imaging mass spectrometry, and multiplexed immunofluorescence. Custom image registration and integration techniques are used to create cellular and molecular atlases of this organ system. Through careful optimization, we ensure high-quality and reproducible datasets suitable for cross-patient comparisons that are essential to understanding human health and disease. Moreover, each of these steps can be adapted to other organ systems or diseases, enabling additional atlas efforts.
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http://dx.doi.org/10.1016/j.xpro.2021.100747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371244PMC
September 2021

Construction of a Multi-Phase Contrast Computed Tomography Kidney Atlas.

Proc SPIE Int Soc Opt Eng 2021 15;11596. Epub 2021 Feb 15.

Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA 37212.

The Human BioMolecular Atlas Program (HuBMAP) seeks to create a molecular atlas at the cellular level of the human body to spur interdisciplinary innovations across spatial and temporal scales. While the preponderance of effort is allocated towards cellular and molecular scale mapping, differentiating and contextualizing findings within tissues, organs and systems are essential for the HuBMAP efforts. The kidney is an initial organ target of HuBMAP, and constructing a framework (or atlas) for integrating information across scales is needed for visualizing and integrating information. However, there is no abdominal atlas currently available in the public domain. Substantial variation in healthy kidneys exists with sex, body size, and imaging protocols. With the integration of clinical archives for secondary research use, we are able to build atlases based on a diverse population and clinically relevant protocols. In this study, we created a computed tomography (CT) phase-specific atlas for the abdomen, which is optimized for the kidney organ. A two-stage registration pipeline was used by registering extracted abdominal volume of interest from body part regression, to a high-resolution CT. Affine and non-rigid registration were performed to all scans hierarchically. To generate and evaluate the atlas, multiphase CT scans of 500 control subjects (age: 15 - 50, 250 males, 250 females) are registered to the atlas target through the complete pipeline. The abdominal body and kidney registration are shown to be stable with the variance map computed from the result average template. Both left and right kidneys are substantially localized in the high-resolution target space, which successfully demonstrated the sharp details of its anatomical characteristics across each phase. We illustrated the applicability of the atlas template for integrating across normal kidney variation from 64 cm to 302 cm.
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http://dx.doi.org/10.1117/12.2580561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336653PMC
February 2021

Assessment of the Banff Working Group classification of definitive BK polyomavirus nephropathy.

Transpl Int 2021 Nov 2;34(11):2286-2296. Epub 2021 Sep 2.

Department of Medicine, Division of Nephrology, Eastern Virginia Medical School, Norfolk, VA, USA.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.
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http://dx.doi.org/10.1111/tri.14003DOI Listing
November 2021

Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seq.

Diabetes 2021 10 7;70(10):2377-2390. Epub 2021 Jul 7.

Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, TN

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26; eNOS; mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26; eNOS mice using translating ribosome affinity purification (TRAP) and RNA-seq. More than 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN than in T1DN. TGF-β signaling pathway genes were upregulated, while MAPK pathway genes were downregulated only in T2DN, while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased, while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number of diabetes-induced genes not previously linked to podocyte injury were confirmed in both mouse and human DN. On the basis of differences and similarities in the podocyte translatome in T2DN and T1DN, investigators can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury.
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http://dx.doi.org/10.2337/db21-0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576501PMC
October 2021

Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology.

ASAIO J 2021 10;67(10):1087-1096

Departments of Medicine and Biomedical Engineering, Sarver Heart Center, University of Arizona, Tucson, Arizona.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.
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http://dx.doi.org/10.1097/MAT.0000000000001530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478105PMC
October 2021

Kidney injury-mediated disruption of intestinal lymphatics involves dicarbonyl-modified lipoproteins.

Kidney Int 2021 09 5;100(3):585-596. Epub 2021 Jun 5.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

Kidney disease affects intestinal structure and function. Although intestinal lymphatics are central in absorption and remodeling of dietary and synthesized lipids/lipoproteins, little is known about how kidney injury impacts the intestinal lymphatic network, or lipoproteins transported therein. To study this, we used puromycin aminoglycoside-treated rats and NEP25 transgenic mice to show that proteinuric injury expanded the intestinal lymphatic network, activated lymphatic endothelial cells and increased mesenteric lymph flow. The lymph was found to contain increased levels of cytokines, immune cells, and isolevuglandin (a highly reactive dicarbonyl) and to have a greater output of apolipoprotein AI. Plasma levels of cytokines and isolevuglandin were not changed. However, isolevuglandin was also increased in the ileum of proteinuric animals, and intestinal epithelial cells exposed to myeloperoxidase produced more isolevuglandin. Apolipoprotein AI modified by isolevuglandin directly increased lymphatic vessel contractions, activated lymphatic endothelial cells, and enhanced the secretion of the lymphangiogenic promoter vascular endothelial growth factor-C by macrophages. Inhibition of isolevuglandin synthesis by a carbonyl scavenger reduced intestinal isolevuglandin adduct level and lymphangiogenesis. Thus, our data reveal a novel mediator, isolevuglandin modified apolipoprotein AI, and uncover intestinal lymphatic network structure and activity as a new pathway in the crosstalk between kidney and intestine that may contribute to the adverse impact of kidney disease on other organs.
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http://dx.doi.org/10.1016/j.kint.2021.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447488PMC
September 2021

Does a preclinical randomized controlled trial, pRCT, resolve the gap between animal studies and human trials?

Kidney Int 2021 06;99(6):1262-1264

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

In drug development, preclinical studies using laboratory animals are crucial to test efficacy and safety of drug candidates. However, there have been discrepancies between animal studies and clinical trials in human patients. Preclinical randomized controlled trials, as reported by Lei et al. in this issue of Kidney International, may reduce the gap between experimental studies and randomized controlled trials in human patients, although there remain issues to be addressed.
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http://dx.doi.org/10.1016/j.kint.2021.01.021DOI Listing
June 2021
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