Publications by authors named "Surya V Seshan"

92 Publications

Nicotine, Smoking, Podocytes and Diabetic Nephropathy.

Am J Physiol Renal Physiol 2021 Jan 18. Epub 2021 Jan 18.

University of Miami.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (EC). Podocytes (POD) are essential to preserve the structure and function of the glomerular filtration barrier and strong evidence indicates that early POD loss promotes DN progression. We performed studies in human POD and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and EC activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by COX2, known to induce podocyte injury; downregulation of AMPK, important for maintaining cellular energy stores and antioxidation and upregulation of CD36 that increased lipid uptake and promoted apoptosis. In diabetic mice NIC increased proteinuria, a recognized marker of CKD progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of POD cytoskeleton and increased fibronectin expression. These novel studies critically implicate NIC itself as a contributor to DN progression in CS and EC users.
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http://dx.doi.org/10.1152/ajprenal.00194.2020DOI Listing
January 2021

Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Clin Transplant 2021 Feb 21;35(2):e14200. Epub 2021 Jan 21.

Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.
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http://dx.doi.org/10.1111/ctr.14200DOI Listing
February 2021

Development of New International Antiphospholipid Syndrome Classification Criteria Phase I/II Report: Generation and Reduction of Candidate Criteria.

Arthritis Care Res (Hoboken) 2020 Nov 30. Epub 2020 Nov 30.

Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery; Weill Cornell Medicine, New York, NY, USA.

Objectives: An international multi-disciplinary initiative, jointly supported by American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR), is underway to develop new rigorous classification criteria to identify patients with high likelihood of Antiphospholipid Syndrome (APS) for research purposes. We applied an evidence- and consensus- based approach to identify candidate criteria and develop a hierarchical organization of criteria within domains.

Methods: During Phase I, the APS classification criteria Steering Committee used systematic literature reviews and surveys of international APS physician scientists to generate a comprehensive list of items related to APS. In Phase II, we reviewed the literature, administered surveys, formed domain subcommittees, and used Delphi exercises and nominal group technique to reduce potential APS candidate criteria. Candidate criteria were hierarchically organized into clinical and laboratory domains.

Results: Phase I generated 152 candidate criteria, expanded to 261 items with the addition of subgroups and candidate criteria with potential negative weights. Using iterative item reduction techniques in Phase II, we initially reduced these items to 64 potential candidate criteria organized into ten clinical and laboratory domains. Subsequent item reduction methods resulted in 27 candidate criteria, hierarchically organized into six additive domains (laboratory, macrovascular, microvascular, obstetric, cardiac, and hematologic) for APS classification.

Conclusion: Using data- and consensus-driven methodology, we identified twenty-seven APS candidate criteria in six clinical or laboratory domains. In the next phase, the proposed candidate criteria will be used for real-world case collection and further refined, organized, and weighted to determine an aggregate score and threshold for APS classification.
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http://dx.doi.org/10.1002/acr.24520DOI Listing
November 2020

Autopsy Findings in 32 Patients with COVID-19: A Single-Institution Experience.

Pathobiology 2021 17;88(1):56-68. Epub 2020 Sep 17.

Weill Cornell Medicine, New York, New York, USA,

Background: A novel coronavirus, SARS-CoV-2, was identified in Wuhan, China in late 2019. This virus rapidly spread around the world causing disease ranging from minimal symptoms to severe pneumonia, which was termed coronavirus disease (i.e., COVID). Postmortem examination is a valuable tool for studying the pathobiology of this new infection.

Methods: We report the clinicopathologic findings from 32 autopsy studies conducted on patients who died of COVID-19 including routine gross and microscopic examination with applicable special and immunohistochemical staining techniques.

Results: SARS-CoV-2 infection was confirmed by nasopharyngeal RT-PCR in 31 cases (97%) and by immunohistochemical staining for SARS-CoV-2 spike-protein in the lung in the remaining 1 case (3%). The ethnically diverse cohort consisted of 22 males and 10 females with a mean age of 68 years (range: 30-100). Patients most commonly presented with cough (17 [55%]), shortness of breath (26 [81%]), and a low-grade fever (17 [55%]). Thirty-one (97%) of the patients had at least 1 comorbidity (mean = 4). Twenty-eight patients (88%) had widespread thromboembolic disease, as well as diffuse alveolar damage (30 [94%]), diabetic nephropathy (17 [57%]) and acute tubular injury. Patterns of liver injury were heterogeneous, featuring 10 (36%) with frequent large basophilic structures in sinusoidal endothelium, and increased immunoblast-like cells in lymph nodes.

Conclusion: This series of autopsies from patients with COVID-19 confirms the observation that the majority of severely affected patients have significant pulmonary pathology. However, many patients also have widespread microscopic thromboses, as well as characteristic findings in the liver and lymph nodes.
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http://dx.doi.org/10.1159/000511325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573917PMC
February 2021

COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City.

Mod Pathol 2020 11 2;33(11):2156-2168. Epub 2020 Sep 2.

Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

SARS-CoV-2, the etiologic agent of COVID-19, is a global pandemic with substantial mortality dominated by acute respiratory distress syndrome. We systematically evaluated lungs of 68 autopsies from 3 institutions in heavily hit areas (2 USA, 1 Italy). Detailed evaluation of several compartments (airways, alveolar walls, airspaces, and vasculature) was performed to determine the range of histologic features. The cohort consisted of 47 males and 21 females with a median age of 73 years (range 30-96). Co-morbidities were present in most patients with 60% reporting at least three conditions. Tracheobronchitis was frequently present, independent from intubation or superimposed pneumonia. Diffuse alveolar damage (DAD) was seen in 87% of cases. Later phases of DAD were less frequent and correlated with longer duration of disease. Large vessel thrombi were seen in 42% of cases but platelet (CD61 positive) and/or fibrin microthrombi were present at least focally in 84%. Ultrastructurally, small vessels showed basal membrane reduplication and significant endothelial swelling with cytoplasmic vacuolization. In a subset of cases, virus was detected using different tools (immunohistochemistry for SARS-CoV-2 viral spike protein, RNA in situ hybridization, lung viral culture, and electron microscopy). Virus was seen in airway epithelium and type 2 pneumocytes. IHC or in situ detection, as well as viable form (lung culture positive) was associated with the presence of hyaline membranes, usually within 2 weeks but up to 4 weeks after initial diagnosis. COVID-19 pneumonia is a heterogeneous disease (tracheobronchitis, DAD, and vascular injury), but with consistent features in three centers. The pulmonary vasculature, with capillary microthrombi and inflammation, as well as macrothrombi, is commonly involved. Viral infection in areas of ongoing active injury contributes to persistent and temporally heterogeneous lung damage.
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http://dx.doi.org/10.1038/s41379-020-00661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463226PMC
November 2020

Consensus definitions for glomerular lesions by light and electron microscopy: recommendations from a working group of the Renal Pathology Society.

Kidney Int 2020 11 29;98(5):1120-1134. Epub 2020 Aug 29.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.
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http://dx.doi.org/10.1016/j.kint.2020.08.006DOI Listing
November 2020

Transcription factor 21 expression in injured podocytes of glomerular diseases.

Sci Rep 2020 07 13;10(1):11516. Epub 2020 Jul 13.

Department of Nephrology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.

Transcription factor 21 (TCF21) is one of the essential transcription factors in kidney development. To elucidate its influence on glomerular disease, we have investigated TCF21 expression in human and rat kidney tissue, and its urinary concentration. Immunohistological analysis suggested the highest TCF21 expression in nephrotic syndrome along with the urinary protein level. Urinary TCF21 concentration in human showed a positive correlation with its podocyte expression level. In nephrotic rat models, TCF21 expression in podocytes increased along with the severity of nephrotic syndrome. Next, in vitro experiments using Tcf21-expressing murine podocyte cell line, we could observe some Tcf21-dependent effects, related with actin cytoskeleton dysregulation and apoptosis. Our study illustrated TCF21 expression changes in vivo and its in vitro-functional significance injured podocytes.
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http://dx.doi.org/10.1038/s41598-020-68422-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359327PMC
July 2020

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era.

Am J Transplant 2021 02 5;21(2):669-680. Epub 2020 Aug 5.

Department of Pathology, Weill-Cornell Medical Center/ New York Presbyterian Hospital, New York, New York, USA.

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter "modern-era" validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.
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http://dx.doi.org/10.1111/ajt.16189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891590PMC
February 2021

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

Am J Kidney Dis 2020 09 28;76(3):374-383. Epub 2020 Apr 28.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.

Rationale & Objectives: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood.

Study Design: Multicenter case series.

Setting & Participants: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls.

Findings: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence.

Limitations: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies.

Conclusions: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.
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http://dx.doi.org/10.1053/j.ajkd.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483441PMC
September 2020

Urinary cell transcriptomics and acute rejection in human kidney allografts.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

BACKGROUNDRNA sequencing (RNA-Seq) is a molecular tool to analyze global transcriptional changes, deduce pathogenic mechanisms, and discover biomarkers. We performed RNA-Seq to investigate gene expression and biological pathways in urinary cells and kidney allograft biopsies during an acute rejection episode and to determine whether urinary cell gene expression patterns are enriched for biopsy transcriptional profiles.METHODSWe performed RNA-Seq of 57 urine samples collected from 53 kidney allograft recipients (patients) with biopsies classified as acute T cell-mediated rejection (TCMR; n = 22), antibody-mediated rejection (AMR; n = 8), or normal/nonspecific changes (No Rejection; n = 27). We also performed RNA-Seq of 49 kidney allograft biopsies from 49 recipients with biopsies classified as TCMR (n = 12), AMR (n = 17), or No Rejection (n = 20). We analyzed RNA-Seq data for differential gene expression, biological pathways, and gene set enrichment across diagnoses and across biospecimens.RESULTSWe identified unique and shared gene signatures associated with biological pathways during an episode of TCMR or AMR compared with No Rejection. Gene Set Enrichment Analysis demonstrated enrichment for TCMR biopsy signature and AMR biopsy signature in TCMR urine and AMR urine, irrespective of whether the biopsy and urine were from the same or different patients. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of immune cell types in urinary cells compared with biopsies.CONCLUSIONSRNA-Seq of urinary cells and biopsies, in addition to identifying enriched gene signatures and pathways associated with TCMR or AMR, revealed genomic changes between TCMR and AMR, as well as between allograft biopsies and urinary cells.
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http://dx.doi.org/10.1172/jci.insight.131552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101135PMC
February 2020

Glomerular, Mesangial, and Tubular Cytoplasmic Fibrillary Inclusions in a Patient with Light-Chain Proximal Tubulopathy.

Nephron 2020 4;144(4):190-194. Epub 2020 Feb 4.

Department of Nephrology, The Mater Hospital, North Sydney, New South Wales, Australia.

Monoclonal immunoglobulin or free light chains, produced in the setting of plasma cell dyscrasias, are a common cause of kidney injury with a wide variety of disease patterns. Light-chain proximal tubulopathy is a rare form of this disease that is often difficult to diagnose due to its relatively indolent presentation, subtle light microscopic findings, and often negative immunofluorescence using routine laboratory techniques. We report a case of light-chain proximal tubulopathy with cytoplasmic fibrillary inclusions in tubular cells, glomerular endothelial cells, and mesangial cells, which were positive for κ light chains on immunostaining after pronase digestion. Cytoplasmic fibrillary inclusions, composed of monoclonal protein, are strongly suggestive of underlying plasma cell dyscrasias, and such cases warrant further hematological investigations.
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http://dx.doi.org/10.1159/000505029DOI Listing
February 2020

The Case | Knee pain and allograft dysfunction in a kidney transplant recipient.

Kidney Int 2020 02;97(2):429-430

Division of Nephrology and Hypertension, Weill Cornell Medical Center, New York-Presbyterian Hospital, New York, New York, USA.

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http://dx.doi.org/10.1016/j.kint.2019.07.007DOI Listing
February 2020

Landscape of innate immune system transcriptome and acute T cell-mediated rejection of human kidney allografts.

JCI Insight 2019 07 11;4(13). Epub 2019 Jul 11.

Division of Nephrology and Hypertension, Department of Medicine.

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.
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http://dx.doi.org/10.1172/jci.insight.128014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629252PMC
July 2019

Bortezomib for Reduction of Proteinuria in IgA Nephropathy.

Kidney Int Rep 2018 Jul 11;3(4):861-866. Epub 2018 Mar 11.

Department of Medicine, Division of Nephrology and Hypertension, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, USA.

Introduction: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria.

Methods: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day.

Results: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease.

Conclusion: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.
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http://dx.doi.org/10.1016/j.ekir.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035125PMC
July 2018

Single nucleotide variant counts computed from RNA sequencing and cellular traffic into human kidney allografts.

Am J Transplant 2018 10 15;18(10):2429-2442. Epub 2018 May 15.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York.

Advances in bioinformatics allow identification of single nucleotide polymorphisms (variants) from RNA sequence data. In an allograft biopsy, 2 genomes contribute to the RNA pool, 1 from the donor organ and the other from the infiltrating recipient's cells. We hypothesize that imbalances in genetic variants of RNA sequence data of kidney allograft biopsies provide an objective measure of cellular infiltration of the allograft. We performed mRNA sequencing of 40 kidney allograft biopsies, selected to represent a comprehensive range of diagnostic categories. We analyzed the sequencing reads of these biopsies and of 462 lymphoblastoid cell lines from the 1000 Genomes Project, for RNA variants. The ratio of heterozygous to nonreference genome homozygous variants (Het/Hom ratio) on all autosomes was determined for each sample, and the estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) score was computed as a complementary estimate of the degree of cellular infiltration into biopsies. The Het/Hom ratios (P = .02) and the ESTIMATE scores (P < .001) were associated with the biopsy diagnosis. Both measures correlated significantly (r = .67, P < .0001), even though the Het/Hom ratio is based on mRNA sequence variation, while the ESTIMATE score uses mRNA expression. Het/Hom ratio and the ESTIMATE score may offer unbiased and quantitative parameters for characterizing cellular traffic into human kidney allografts.
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http://dx.doi.org/10.1111/ajt.14870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160347PMC
October 2018

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.

Kidney Int 2018 04 16;93(4):789-796. Epub 2018 Feb 16.

Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.
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http://dx.doi.org/10.1016/j.kint.2017.11.023DOI Listing
April 2018

The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations.

J Am Soc Nephrol 2018 02 26;29(2):680-693. Epub 2017 Dec 26.

Department of Pathology, Weill Cornell Medicine, New York, New York.

Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis.
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http://dx.doi.org/10.1681/ASN.2017050477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791071PMC
February 2018

Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study.

Clin Transplant 2017 Nov;31(11)

Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA.

We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid-free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein ≥1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine ≤1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.
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http://dx.doi.org/10.1111/ctr.13117DOI Listing
November 2017

Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone.

Obes Res Clin Pract 2017 Sep - Oct;11(5):597-606. Epub 2017 Apr 22.

Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Objective: Patients with obesity are at risk for chronic kidney disease. The aim is to characterize the spectrum of kidney disease in these patients, which may be related to obesity, termed obesity-related glomerulopathy (ORG), or may have other diseases secondary to associated or unassociated medical conditions.

Methods: Native kidney biopsies from 2000 to 2012 were retrospectively reviewed from all patients with body mass index >30kg/m. Glomerular diameter was measured using a standard micrometer and clinicopathologic characteristics were analyzed.

Results: 4% (287) of all biopsies were obtained from patients with obesity (mean: weight 122kg, BMI 40.4±7.35kg/m) for proteinuria in 93% and renal insufficiency in 53%. Frequent associated factors were abnormal glucose metabolism (31%), hypertension (60%), and obstructive sleep apnea (9%). Typical lesions of ORG were seen in 41% of cases and additional diseases in the rest. Glomerulomegaly, glomerular diameter >180μm, was present in 84% of cases (mean 224μm) vs normal size in 11% (mean 157μm), but was not increased with higher magnitude of obesity. Proteinuria was highest in patients with idiopathic FSGS (mean 8g/24h) and immune complex diseases (mean 7.4g/24h) and was mainly subnephrotic in obesity-related FSGS and tubulo-interstitial diseases. Creatinine levels were highest in tubulointerstitial diseases (mean 8.4mg/dL) and progressive diabetic nephropathy (mean 2.5mg/dL).

Conclusions: Diverse kidney pathology superimposed on ORG is present in patients with obesity with varied clinical renal disease, some of which may be amenable for therapy. Kidney biopsy will assist in delineating these lesions for appropriate management and prognosis.
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http://dx.doi.org/10.1016/j.orcp.2017.04.003DOI Listing
June 2018

A proposal for standardized grading of chronic changes in native kidney biopsy specimens.

Kidney Int 2017 04;91(4):787-789

Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade.
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http://dx.doi.org/10.1016/j.kint.2017.01.002DOI Listing
April 2017

Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1 and IL-18 and Arrests CKD.

J Am Soc Nephrol 2017 May 23;28(5):1437-1449. Epub 2016 Nov 23.

Institute of Advanced Materials, Devices, and Nanotechnology, and.

The innate immune system has been implicated in both AKI and CKD. Damaged mitochondria release danger molecules, such as reactive oxygen species, DNA, and cardiolipin, which can cause NLRP3 inflammasome activation and upregulation of IL-18 and IL-1 It is not known if mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation. We conducted a 9-month study in Sprague-Dawley rats after 45 minutes of bilateral renal ischemia. We detected glomerular and peritubular capillary rarefaction, macrophage infiltration, and fibrosis at 1 month. Transmission electron microscopy revealed mitochondrial degeneration, mitophagy, and deformed foot processes in podocytes. These changes progressed over the study period, with a persistent increase in renal cortical expression of IL-18, IL-1, and TGF-, despite a gradual decline in TNF- expression and macrophage infiltration. Treatment with a mitoprotective agent (SS-31; elamipretide) for 6 weeks, starting 1 month after ischemia, preserved mitochondrial integrity, ameliorated expression levels of all inflammatory markers, restored glomerular capillaries and podocyte structure, and arrested glomerulosclerosis and interstitial fibrosis. Further, helium ion microscopy vividly demonstrated the restoration of podocyte structure by SS-31. The protection by SS-31 was sustained for ≥6 months after treatment ended, with normalization of IL-18 and IL-1 expression. These results support a role for mitochondrial damage in inflammasome activation and CKD and suggest mitochondrial protection as a novel therapeutic approach that can arrest the progression of CKD. Notably, SS-31 is effective when given long after AKI and provides persistent protection after termination of drug treatment.
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http://dx.doi.org/10.1681/ASN.2016070761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407729PMC
May 2017

Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I Interferon in Patients With Systemic Autoimmune Disease.

Arthritis Rheumatol 2016 11;68(11):2686-2696

Hospital for Special Surgery, New York, New York.

Objective: Increased expression of type I interferon (IFN) and a broad signature of type I IFN-induced gene transcripts are observed in patients with systemic lupus erythematosus (SLE) and other systemic autoimmune diseases. To identify disease-relevant triggers of the type I IFN pathway, this study sought to investigate whether endogenous virus-like genomic repeat elements, normally silent, are expressed in patients with systemic autoimmune disease, and whether these retroelements could activate an innate immune response and induce type I IFN.

Methods: Expression of type I IFN and long interspersed nuclear element 1 (LINE-1; L1) was studied by polymerase chain reaction, Western blotting, and immunohistochemistry in samples of kidney tissue from patients with lupus nephritis and minor salivary gland (MSG) tissue from patients with primary Sjögren's syndrome (SS). Induction of type I IFN by L1 was investigated by transfection of plasmacytoid dendritic cells (PDCs) or monocytes with an L1-encoding plasmid or L1 RNA. Involvement of innate immune pathways and altered L1 methylation were assessed.

Results: Levels of L1 messenger RNA transcripts were increased in lupus nephritis kidneys and in MSG tissue from patients with SS. Transcript expression correlated with the expression of type I IFN and L1 DNA demethylation. L1 open-reading frame 1/p40 protein and IFNβ were expressed in MSG ductal epithelial cells and in lupus nephritis kidneys, and IFNα was detected in infiltrating PDCs. Transfection of PDCs or monocytes with L1-encoding DNA or RNA induced type I IFN. Inhibition of Toll-like receptor 7 (TLR-7)/TLR-8 reduced the induction of IFNα by L1 in PDCs, and an inhibitor of IKKε/TANK-binding kinase 1 abrogated the induction of type I IFN by L1 RNA in monocytes.

Conclusion: L1 genomic repeat elements represent endogenous nucleic acid triggers of the type I IFN pathway in SLE and SS and may contribute to initiation or amplification of autoimmune disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083133PMC
http://dx.doi.org/10.1002/art.39795DOI Listing
November 2016

Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury.

Kidney Int 2016 11 9;90(5):997-1011. Epub 2016 Aug 9.

Department of Pathology, Weill Cornell Medical College, New York, New York, USA.

Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-β) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.
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http://dx.doi.org/10.1016/j.kint.2016.06.013DOI Listing
November 2016

OCULAR MANIFESTATIONS OF MONOCLONAL IMMUNOGLOBULIN LIGHT CHAIN DEPOSITION DISEASE.

Retin Cases Brief Rep 2017 Fall;11(4):310-315

*Vitreous Retina Macula Consultants of New York, New York, New York, The LuEsther T. Mertz Retinal Research Center, Manhattan Eye Ear and Throat Hospital, New York, New York; †Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University, College of Physicians and Surgeons, New York, New York; ‡Department of Ophthalmology, New York University School of Medicine, New York, New York; §Retina Associates of New York; and ¶Department of Pathology, Weill Cornell Medical College, New York, New York.

Purpose: To demonstrate unusual retinal findings in a patient with progressive renal failure due to idiopathic monoclonal immunoglobulin light chain deposition disease, using multimodal imaging.

Methods: Observational case report of a 43-year-old white man with renal failure due to light chain deposition disease. His course over 6 years was documented with multimodal imaging including fundus photography, fundus autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography. Additional evaluations included ocular ultrasound, electroretinography, positron emission tomography, serum protein electrophoreses, skeletal surveys to detect osteolytic lesions, and renal, liver, and rectal biopsies in search of amyloid.

Results: The patient's ocular course mirrored the severity of his renal dysfunction for which he required a renal transplant. Changes observed in the native kidney recurred in the transplant 2 years later, as evidenced by immunohistochemistry, revealing thick linear deposits of kappa chains, with no complement, overlying the glomerular basement membrane. The systemic workup was negative for amyloid but showed an overwhelming ratio of kappa to lambda light chains on serum protein electrophoreses and no clinical signs of plasma cell dyscrasias, all consistent with idiopathic light chain deposition disease. The patient presented with a generalized, bilateral "leopard-spot" fundus appearance on fundus autofluorescence, striking globular subretinal deposits on spectral domain optical coherence tomography, and subfoveal subretinal fluid without retinal pigment epithelium detachment or choroidal effusions. The subfoveal fluid did not respond to intravitreal injections of antiangiogenic agents or steroids but resolved after renal transplantation. A temporary posttransplant visual improvement was associated with lessening of the subretinal drusenoid deposits demonstrated by multimodal imaging. The terminal vision deterioration was associated with amorphous, vitelliform-like material deposition and atrophic changes.

Conclusion: This case may illustrate a resemblance in the renal glomerulus basement membrane and retinal pigment epithelium-Bruch membrane complex, because the authors observed deposits of excess monoclonal kappa chains manifesting as extracellular, proteinaceous aggregates on the basement membrane of the glomerulus, and striking, globular subretinal deposits that overlay a thickened retinal pigment epithelium-Bruch membrane complex. The ocular lesions' refractoriness to intravitreal treatments could be attributed to the fact that they represent proteinaceous aggregates similar to those documented in the glomeruli. This is the first report of generalized, large, subretinal drusenoid deposits and their course, as documented through multimodal imaging, paralleling the chronology of systemic changes in a patient with light chain deposition disease.
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http://dx.doi.org/10.1097/ICB.0000000000000351DOI Listing
January 2018

Polyoma (BK) virus associated urothelial carcinoma originating within a renal allograft five years following resolution of polyoma virus nephropathy.

Clin Nephrol 2016 Mar;85(3):179-83

A direct role for BK polyomavirus infection in malignant tumors of renal allografts and urinary tract is emerging. Case reports suggest a link between BK virus (BKV) reactivation and development of malignancy in renal allograft recipients. Herein we describe the first case of BKV positive invasive urothelial carcinoma within the renal allograft, presenting with chronic diarrhea and weight loss 5 years following resolution of BK viremia/nephropathy (BKVN). Unique to our case was the remote history of BK viremia/BKVN, rising titer of anti-HLA antibody and presence of renal limited urothelial carcinoma with microinvasion of malignant cells staining positive for SV40 large T antigen (T-Ag). These findings suggest that persistence of subclinical BKV infection within the renal allograft may play a role in the malignant transformation of epithelial cells. Patients with history of BKVN may be at risk for kidney and urinary tract malignancy despite resolution of BK viremia/BKVN.
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http://dx.doi.org/10.5414/CN108410DOI Listing
March 2016

Minimal change disease: an unusual presentation of marginal zone MALT lymphoma.

Clin Nephrol 2016 Mar;85(3):184-8

Minimal change disease (MCD) in association with low-grade extra-nodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) (MALT lymphoma) is a rare clinicopathologic entity. We report a 68-year-old male who presented with nephrotic range proteinuria as the first manifestation of underlying MZL, confirmed with standard set of investigations. Being a steroid non-responder, he was treated with rituximab demonstrating a marked response with resolution of proteinuria. However, he relapsed after 3 months. Upon relapse, a combination of rituximab and bendamustine (R-Benda) was initiated achieving sustained resolution of proteinuria. No additional treatment was administered and the proteinuria has remained in remission for over a year.
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http://dx.doi.org/10.5414/CN108593DOI Listing
March 2016

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN.

J Am Soc Nephrol 2016 May 13;27(5):1278-87. Epub 2015 Nov 13.

Mayo Clinic, Rochester, Minnesota.

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN.
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http://dx.doi.org/10.1681/ASN.2015060612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849835PMC
May 2016