Publications by authors named "Steven P Salvatore"

20 Publications

  • Page 1 of 1

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

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.

Blood 2020 09;136(10):1169-1179

Molecular Medicine Program and.

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.
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http://dx.doi.org/10.1182/blood.2020007008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472714PMC
September 2020

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.

Cell 2020 07 27;182(2):429-446.e14. Epub 2020 May 27.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.
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http://dx.doi.org/10.1016/j.cell.2020.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250779PMC
July 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

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

Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol 2018 08 24;29(8):2139-2156. Epub 2018 Jul 24.

Departments of Pathology and Laboratory Medicine,

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in and that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.

Methods: We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in and genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in or was identified.

Results: Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of or were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No -heterozygous mutations of or genes were identified. Copy number changes of ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non- genes, including other ciliopathy genes and cancer-related genes.

Conclusions: These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of or in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.
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http://dx.doi.org/10.1681/ASN.2017080878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065086PMC
August 2018

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

Papillary renal cell carcinoma with a somatic mutation in MET in a patient with autosomal dominant polycystic kidney disease.

Cancer Genet 2016 Jan-Feb;209(1-2):11-20. Epub 2015 Dec 1.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 and is characterized by proliferation of renal tubular epithelium and progressive chronic kidney disease. Derangements in similar cellular signaling pathways occur in ADPKD and renal malignancies, although an association of these disorders has not been established. Herein, we present a case of papillary RCC (pRCC) incidentally discovered in a patient with ADPKD following bilateral native nephrectomy during renal transplantation. Whole exome sequencing of the pRCC found a somatic missense mutation in MET proto-oncogene, p.Val1110Ile, not present in kidney cyst epithelium or non-cystic tissue. RNA sequencing demonstrated increased mRNA expression of MET and pathway-related genes, but no significant copy number variation of MET was detected. Genetic analysis of PKD genes from peripheral blood lymphocytes and renal cyst epithelium identified a constitutional PKD1 germline mutation, p.Trp1582Ser, predicted to be pathogenic. Unique somatic mutations in PKD1 were also detected in 80% of the renal cysts analyzed, but not in the pRCC. These results suggest that, in this patient, the pRCC utilized a signaling pathway involving MET that was distinct from the pathogenesis of ADPKD. This is the first report of PKD1 mutations and a somatic mutation of the MET oncogene in a pRCC in ADPKD.
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http://dx.doi.org/10.1016/j.cancergen.2015.11.002DOI Listing
June 2016

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

Smoking-related glomerulopathy: expanding the morphologic spectrum.

Am J Nephrol 2015 5;41(1):66-72. Epub 2015 Feb 5.

Weill Cornell Medical College, New York, N.Y., USA.

Background: Chronic smoking and hypertension may lead to smoking-related nodular glomerulopathy (SRNG), a well-recognized entity that clinically and pathologically mimics nodular diabetic nephropathy (DN). However, like DN, diffuse mesangial sclerosis may occur in this setting without nodules.

Methods: The clinicopathologic features of 10 non-diabetic patients with a long smoking history diagnosed from 2003-2012 showing diffuse mesangial glomerulosclerosis (6) or SRNG (4) were analyzed.

Results: Nine of 10 patients were men, aged 58-80 with a 20-58 pack-year smoking history. None of the patients manifested diabetes, but all of them had hypertension. Numerous other cardiovascular comorbidities were present. At biopsy, the mean creatinine was 1.9 mg/dl (range 1.4-3) and the mean proteinuria was 3.9 g/24 h. The renal pathologic findings were similar in all patients except mesangial nodules in SRNG. Global glomerulosclerosis was seen in 6-72% of glomeruli (mean 31%), glomerulomegaly in all cases, and a range of interstitial fibrosis in 10-70% (mean 43%). Moderate (40%) and severe (50%) arteriosclerosis and arteriolar hyalinosis (80%) were also observed. Glomerular hilar or mesangial neovascularization was prominent. Endothelial swelling, subendothelial widening, and new basement membrane formation suggesting chronic healing thrombotic microangiopathy (TMA) was noted in 80%. No immune complexes were localized.

Conclusions: Kidney biopsies from patients with proteinuria and chronic renal insufficiency in the setting of prolonged smoking and hypertension show either diffuse or nodular mesangial glomerulosclerosis. Chronic glomerular mesangial and endothelial injury associated with smoking leads to a chronic TMA appearance in the appropriate setting, even in the absence of mesangial nodule formation.
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http://dx.doi.org/10.1159/000371727DOI Listing
September 2015

Evaluating the cause of death in obese individuals: a ten-year medical autopsy study.

J Obes 2015 14;2015:695374. Epub 2015 Jan 14.

NewYork-Presbyterian Hospital, Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, 525 East 68th Street, New York, NY 10065, USA.

Background: Obesity is a growing public health problem associated with increased morbidity and rate of death. Postmortem examination is imperative to determine the cause of death, to detect clinically unsuspected disease entities, and consequently to determine the actual impact of obesity on patient mortality.

Methods: A total of 849 adult autopsies were retrospectively reviewed. Obese (BMI ≥ 30 kg/m(2)) and nonobese patients were separately studied. The primary cause of death in each group was categorized into malignancy, infection, stroke, ischemic and nonischemic heart disease, pulmonary embolism, hemorrhage, and primary nonneoplastic diseases of different organ systems.

Results: Of 849 autopsies, 32.3% were obese. The leading causes of death in the obese population were malignancy (31.4%), infection (25.9%), ischemic heart disease (12.8%), and pulmonary embolism (6.2%). Obese individuals were statistically more likely to die from pulmonary embolism and liver disease and less likely to die from neurologic diseases and nonischemic heart disease.

Conclusion: Autopsies on obese individuals constitute a third of all adult medical autopsies in our center. Increased death rates in the obese due to pulmonary embolism and liver disease should receive special clinical attention. Autopsy findings in the obese population should contribute to overall premortem disease detection, prevention, and management.
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http://dx.doi.org/10.1155/2015/695374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310448PMC
September 2015

Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature.

Hum Pathol 2014 Sep 12;45(9):1918-27. Epub 2014 Jun 12.

Department of Pathology, Weill Cornell Medical College, Cornell University, New York, New York, 10065. Electronic address:

Recently, cancer therapies have been supplemented by vascular endothelial growth factor (VEGF) inhibitors as anti-angiogenic agents. However, kidney-related adverse reactions associated with these agents clinically manifest as hypertension and proteinuria, the most severe form being thrombotic microangiopathy (TMA). We present the spectrum of pathological features in VEGF inhibitor-associated kidney disease. Clinicopathological findings of kidney disease were retrospectively studied in 5 cancer patients treated with anti-VEGF agents. Although 4 cases received bevacizumab (anti-VEGF-A), one was given sorafenib (small molecule tyrosine kinase inhibitor affecting VEGF-R2). All patients presented with acute kidney injury, hypertension, and/or proteinuria. All kidney biopsies showed recent and chronic endothelial injury of varying severity and vascular sclerosis, including 2 with typical active features of TMA. Furthermore, acute tubular injury with focal necrosis was seen in all cases. While administration of VEGF inhibitor was discontinued in 4 cases, it was resumed for 5 more doses, following steroid therapy in 1 case. Cessation of VEGF inhibitor therapy was successful in reversing anemia and led to improvement of hypertension and proteinuria in 4 of the 5 cases. One case with TMA progressed to end-stage renal disease. A range of renal pathologic lesions secondary to endothelial injury are noted often accompanied by acute tubular damage following anti-VEGF therapy, the most severe being TMA. While most of the clinical manifestations are reversible with discontinuation of therapy, the role of other nephrotoxic chemotherapeutic agents in enhancing renal injury including severe TMA and other host factors with possible poor outcome should be considered.
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http://dx.doi.org/10.1016/j.humpath.2014.05.015DOI Listing
September 2014

Acute kidney injury due to tubular intraluminal monoclonal light chain crystals mimicking acute pyelonephritis.

Ren Fail 2014 Mar 24;36(2):300-5. Epub 2013 Oct 24.

Department of Nephrology, University of Medicine and Dentistry , New Jersey, Newark, NJ , USA and.

Tubular intraluminal inflammatory cells may be seen in kidney biopsies of patients with pyelonephritis, cell-mediated transplant rejection, autoimmune tubulointerstitial nephritis, allergic reactions, or in association with monoclonal light chain casts. When casts in a native kidney are primarily composed of granulocytes, the cause is most commonly acute pyelonephritis due to an ascending bacterial urinary tract infection. We report a 57-year-old man with acute kidney injury and an intense intraluminal neutrophil response to monoclonal lambda light chain crystal containing casts.
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http://dx.doi.org/10.3109/0886022X.2013.844643DOI Listing
March 2014

Collapsing glomerulopathy superimposed on diabetic nephropathy: insights into etiology of an under-recognized, severe pattern of glomerular injury.

Nephrol Dial Transplant 2014 Feb 29;29(2):392-9. Epub 2013 Sep 29.

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

Background: Collapsing glomerulopathy (CG) represents severe podocyte injury with massive proteinuria, rapid progression and relative resistance to therapy. It is associated with multiple etiologies, including obliterative arteriopathy in transplants. However, its association with diabetic nephropathy (DN) has not been reported.

Methods: Renal biopsies performed in diabetic patients for either increasing proteinuria or deteriorating renal function, or both, were retrospectively reviewed. The clinicopathologic features and immunohistochemical staining of podocytes were analyzed.

Results: Of 534 patients with DN, 26 human immunodeficiency virus (HIV)-negative patients were found to have CG superimposed on DN (5% DN cases). At the time of biopsy, their mean serum creatinine was 3.8 mg/dL and proteinuria was 9.8 g/24 h. Renal biopsy showed CG in 2-30% (mean 16% of glomeruli), with segmental (2%) and global (33%) glomerulosclerosis. DN classification was Class IV-12, III-8, IIb-4 and IIa-2. Vascular sclerosis was moderate (44%) and severe (56%). Extensive arteriolar hyalinosis with >50% luminal stenosis was seen in 85% of cases. Markers of podocyte differentiation were lost, consistent with other types of CG. Cytokeratin was focally positive in 70% and VEGF overexpressed in 43%. Follow-up on 17 patients: 13 developed end-stage renal disease (ESRD) in 7 months from the time of biopsy. The development to ESRD in these patients was more rapid than diabetic controls without CG (P=0.005). The remaining four, 5-24 months follow-up, had an increase in creatinine with stable proteinuria.

Conclusions: CG contributes to an increased level or new onset of proteinuria in DN which may be intractable. CG in DN with advanced vascular hyalinosis is presumably due to ischemic podocyte injury and is of prognostic significance.
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http://dx.doi.org/10.1093/ndt/gft408DOI Listing
February 2014

Phylloides Tumor With Numerous Thanatosomes ("Death Bodies"): A Report of Two Cases and a Study of Thanatosomes in Breast Tumors.

Int J Surg Pathol 2014 Jun 5;22(4):337-42. Epub 2013 Apr 5.

Weill Cornell Medical College, New York, NY, USA.

Thanatosomes, a form of degenerative intracellular hyaline globules, have been described in various neoplastic and nonneoplastic disease processes in several organs. These structures are indicative of apoptotic cell death. Herein, we report 2 cases of malignant phylloides tumor, both of which showed numerous thanatosomes-to the point of dominating the histological appearance and masking the stromal element. Our subsequently conducted study showed that thanatosomes were present in 14 of 86 (16.3%) high-grade malignant breast tumors. The structures were identified in 5/25 (20%) malignant phylloides tumors, 4/19 (21.1%) metaplastic spindle cell carcinomas, 3/21 (14.3%) invasive carcinomas s/p neoadjuvant chemotherapy, and 2/21 (9.5%) poorly differentiated invasive ductal carcinomas. When present, thanatosomes were typically a rare and focal finding in most types of cases. In malignant phylloides tumors, the structures were relatively more numerous when present. Our study shows that although thanatosomes can be present in several types of malignant breast tumors, they are more common in malignant phylloides tumor. Only rarely, as evident from our 2 index cases, do thanatosomes cause diagnostic difficulty.
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http://dx.doi.org/10.1177/1066896913482728DOI Listing
June 2014

Nonneoplastic renal cortical scarring at tumor nephrectomy predicts decline in kidney function.

Arch Pathol Lab Med 2013 Apr;137(4):531-40

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.

Context: Evaluating nontumor portions of tumor nephrectomies is useful to diagnose nonneoplastic renal disease.

Objective: To determine the medical renal disease frequency and to assess the prognostic significance of the various renal pathologic variables with long-term follow-up in tumor nephrectomy patients.

Design: We reviewed nonneoplastic kidney sections of 456 consecutive cases from 1998 to 2008. Seventy-five cases were excluded (19 tumor compression, 25 no nonneoplastic tissue, 22 embolized kidneys, 9 end stage). Special staining, immunofluorescence, and/or electron microscopy was performed where appropriate. Vascular sclerosis was scored from mild to severe; interstitial fibrosis/tubular atrophy and global glomerulosclerosis (GS) were expressed as percentages. Follow-up, minimum 12 months, was evaluated in 156 cases. All renal pathologic variables were compared with regard to change in creatinine level from preoperative assessment to follow-up.

Results: Of 381 cases, 57 had additional medical renal disease (15%), most frequently diabetic nephropathy (28) and hypertensive nephropathy (11). Postoperative creatinine levels increased significantly in patients with severe arteriosclerosis or arteriolosclerosis, >5% GS, and >10% interstitial fibrosis/tubular atrophy. Seventy-four percent of cases with additional nonneoplastic diagnoses showed severe arteriolosclerosis. Higher corresponding GS was seen in the more affected vascular cases: mean, 5.56% GS for mild versus 23% GS for severe. Three patients progressed to renal failure 1 to 4 years after nephrectomy, 2 with hypertensive nephrosclerosis and 1 with diabetic nephropathy.

Conclusions: Medical renal disease was identified in 15% of tumor nephrectomy specimens. The degrees of vascular sclerosis, GS, and interstitial fibrosis/tubular atrophy are predictive of elevated creatinine levels in postnephrectomy patients. Prognostic implications of the nontumor pathology are important in nephrectomized patients.
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http://dx.doi.org/10.5858/arpa.2012-0070-OADOI Listing
April 2013

Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease.

Clin J Am Soc Nephrol 2012 Jun 29;7(6):914-25. Epub 2012 Mar 29.

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

Background And Objectives: Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE.

Design, Setting, Participants, & Measurements: Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy.

Results: Initially, 95% of patients had nephrotic syndrome with proteinuria of 3-12 g per 24 hours, creatinine levels of 0.6-9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%-77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2-3.6 mg/dl with proteinuria of 0.37-4 g per 24 hours.

Conclusions: Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.
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http://dx.doi.org/10.2215/CJN.11751111DOI Listing
June 2012

Pulmonary zygomycoses in an immunosuppressed patient.

Diagn Cytopathol 2011 Jan;39(1):37

Papanicolaou Cytology Laboratory, Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York 10065, USA.

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http://dx.doi.org/10.1002/dc.21317DOI Listing
January 2011