Reproducibility and prognostic ability of chronicity parameters in kidney biopsy - Comprehensive evaluation comparing microscopy and artificial intelligence in digital pathology.

INTRODUCTION: Semi-quantitative scoring of various parameters in renal biopsy is accepted as an important tool to assess disease activity and prognostication. There are concerns on the impact of interobserver variability in its prognostic utility, generating a need for computerized quantification. METHODS: We studied 94 patients with renal biopsies, 45 with native diseases and 49 transplant patients with index biopsies for Polyomavirus nephropathy. Chronicity scores were evaluated using two methods. A standard definition diagram was agreed after international consultation and four renal pathologists scored each parameter in a double-blinded manner. Interstitial fibrosis (IF) score was assessed with five different computerized and AI-based algorithms on trichrome and PAS stains. RESULTS: There was strong prognostic correlation with renal function and graft outcome at a median follow-up ranging from 24 to 42 months respectively, independent of moderate concordance for pathologists scores. IF scores with two of the computerized algorithms showed significant correlation with estimated glomerular filtration rate (eGFR) at biopsy but not at the end of follow-up. There was poor concordance for AI based platforms. CONCLUSION: Chronicity scores are robust prognostic tools despite interobserver reproducibility. AI-algorithms have absolute precision but are limited by significant variation when different hardware and software algorithms are used for quantification.

Vancomycin nephrotoxicity: A comprehensive clinico-pathological study.

INTRODUCTION: Vancomycin, a commonly prescribed antibiotic particularly in the setting of multi-drug resistant infections, is limited by its nephrotoxicity. Despite its common occurrence, much remains unknown on the clinicopathologic profile as well as the pathogenesis of vancomycin nephrotoxicity. Clinical studies included patients often with severe comorbidities and concomitant polypharmacy confounding the causal pathogenesis. Animal models cannot recapitulate this complex clinical situation. Kidney biopsy was not commonly performed. METHODS: To address this limitation, we studied 36 patients who had renal biopsies for acute kidney injury (AKI) for suspicion of vancomycin nephrotoxicity. Detailed renal biopsy evaluation, meticulous evaluation of clinical profiles, and up-to-date follow-up allowed for a diagnostic categorization of vancomycin nephrotoxicity (VNT) in 25 patients and absence of vancomycin nephrotoxicity (NO-VNT) in 11 patients. For careful comparison of these two groups, we proceeded to compile a clinicopathologic and morphologic profiles characteristic for each group. RESULTS: Patients with VNT had a characteristic clinical profile including a common clinical background, a high serum trough level of vancomycin, a rapidly developed and severe acute kidney injury, and a recovery of renal function often shortly after discontinuation of vancomycin. This clinical course was correlated with characteristic renal biopsy findings including acute tubulointerstitial nephritis of allergic type, frequent granulomatous inflammation, concomitant and pronounced acute tubular necrosis of nephrotoxic type, and vancomycin casts, in the absence of significant tubular atrophy and interstitial fibrosis. This clinico-pathologic profile was different from that of patients with NO-VNT, highlighting its role in the diagnosis, management and pathogenetic exploration of vancomycin nephrotoxicity. CONCLUSION: Vancomycin nephrotoxicity has a distinctive morphologic and clinical profile, which should facilitate diagnosis, guide treatment and prognostication, and confer pathogenetic insights.

Myoglobin Cast Nephropathy Diagnosed on Renal Biopsy in a Patient Treated for Malarial Infection.

Myoglobin cast nephropathy occurs in cases of acute renal injury in which large amounts of myoglobin accumulate in the renal tubules, presenting as muscle pain, reddish-brown urine, and elevated creatine kinase levels. Our case describes a 60-year-old male who came to the emergency department with fevers, mild abdominal pain, and constitutional symptoms one day after returning to the United States from a trip to Nigeria. Initial workup demonstrated an acute kidney injury and elevated aminotransferase levels and the patient was started onatovaquone-proguanil for possible malaria given a recent diagnosis in Nigeria. Two days later, the patient was found to have rhabdomyolysis, resulting in a renal biopsy that showed myoglobin cast nephropathy. Previous literature has suggested mechanisms for the development of rhabdomyolysis in malarial infection, including inflammatory processes, direct effect of parasite accumulation, and drug-induced toxicity. Our case further implicates antimalarial therapy as a cause of rhabdomyolysis and increases awareness of myoglobin cast nephropathy as a potential complication of malaria.

ADULT TAPEWORM (PLATYHELMINTHES: CESTODA) PARASITES OF NORTH AMERICAN HERPETOFAUNA: CHECKLIST OF SPECIES AND IDENTIFICATION KEY TO FAMILIES AND GENERA.

An updated checklist of adult tapeworms (Platyhelminthes: Cestoda) that parasitize wild North American amphibians and reptiles is presented: A total of 58 species grouped in 15 genera, 5 families, and 3 orders, are registered; these infect a total of 90 species of reptiles and 88 species of amphibians in the region. An illustrated identification key for the families and genera listed is proposed.

Hyperoxia Disrupts Lung Lymphatic Homeostasis in Neonatal Mice.

Inflammation causes bronchopulmonary dysplasia (BPD), a common lung disease of preterm infants. One reason this disease lacks specific therapies is the paucity of information on the mechanisms regulating inflammation in developing lungs. We address this gap by characterizing the lymphatic phenotype in an experimental BPD model because lymphatics are major regulators of immune homeostasis. We hypothesized that hyperoxia (HO), a major risk factor for experimental and human BPD, disrupts lymphatic endothelial homeostasis using neonatal mice and human dermal lymphatic endothelial cells (HDLECs). Exposure to 70% O2 for 24-72 h decreased the expression of prospero homeobox 1 (Prox1) and vascular endothelial growth factor c (Vegf-c) and increased the expression of heme oxygenase 1 and NAD(P)H dehydrogenase [quinone]1 in HDLECs, and reduced their tubule formation ability. Next, we determined Prox1 and Vegf-c mRNA levels on postnatal days (P) 7 and 14 in neonatal murine lungs. The mRNA levels of these genes increased from P7 to P14, and 70% O2 exposure for 14 d (HO) attenuated this physiological increase in pro-lymphatic factors. Further, HO exposure decreased VEGFR3+ and podoplanin+ lymphatic vessel density and lymphatic function in neonatal murine lungs. Collectively, our results validate the hypothesis that HO disrupts lymphatic endothelial homeostasis.

Rapid Remission of Secondary Membranous Glomerulonephritis Due to Syphilis: A Case Report.

Membranous glomerulonephritis (MGN) is an antibody-mediated autoimmune disease that targets the glomerular basement membrane-podocyte complex, causing defects in the glomerular filtration barrier and resulting in nephrotic syndrome. Management of patients with MGN now relies on identifying the underlying etiology. A 36-year-old female patient, with a recent history of transient vision loss, presented with 11 days of progressive edema and episodes of vomiting, headache, and stomach pain. Evaluation of progressive proteinuria led to a renal biopsy, which showed normal glomerular histology by light microscopy and a full-house pattern of immune-complex deposits by immunofluorescence microscopy. Electron microscopy showing very occasional subepithelial deposits confirmed the diagnosis of MGN. Testing for anti-PLA2R antibody, a biomarker for primary (idiopathic) MGN, was negative by immunohistochemistry and serology. Extensive clinical evaluation and workup led to a rapid plasma reagin (RPR) test for syphilis, which was positive. Treatment was immediately initiated with furosemide, losartan, and weekly intramuscular benzathine penicillin, and within two weeks, the patient's edema had subsided, and her proteinuria had resolved. The patient remained in clinical remission at 11-month follow-up with good overall health. We emphasize the importance of early diagnosis of syphilis-induced MGN as prompt treatment results in rapid remission of renal disease. In the evaluation of secondary MGN, atypical presentations of syphilis should be considered in the differential diagnosis to ensure the timely initiation of appropriate management.

TONGUE WORM (PENTASTOMIDA) PARASITES OF NORTH AMERICAN HERPETOFAUNA: CHECKLIST OF SPECIES, IDENTIFICATION KEY, AND NEW STATE AND HOST RECORDS FROM MEXICO.

An updated checklist of tongue worms (Pentastomida) which parasitize wild North American amphibians and reptiles is presented: a total of 14 species grouped in 6 genera, 4 families, and 2 orders are registered; these infect a total of 58 species of reptiles and 3 amphibians in the region. An illustrated identification key for the taxa listed is proposed. Kiricephalus coarctatus (Diesing, 1860) (Porocephalidae) is recorded for the first time in the snakes Arizona elegans Kennicott, 1859 (Colubridae); Micrurus tener Baird and Girard, 1853 (Elapidae); and Bothrops asper (Garman, 1884) (Viperidae); the exotic Raillietiella taegueselfiRiley, McAllister, and Freed, 1988 (Raillietiellidae) is recorded in the exotic lizard Hemidactylus frenatus Duméril and Bibron, 1836 (Gekkonidae) for the first time, and in Hemidactylus turcicus (Linnaeus, 1758) (Gekkonidae) for the first time in Mexico, this is also the first time it is recorded in a species of lizard native of the Americas, Sceloporus cyanogenys Cope, 1885 (Phrynosomatidae), this latter record represents a parasite spillover event; finally, Porocephalus stilesiSambon, 1910 (Porocephalidae) is formally recorded for the first time in Mexico in the snake Bothrops asper.

Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. METHODS: HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. RESULTS: [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. CONCLUSIONS: [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS.

Papillary Fibroelastoma Incidentally Found on Left Atrial Wall During Minimally Invasive Aortic Valve Replacement.

A 60-year-old man was about to undergo minimally invasive aortic valve replacement when transesophageal echocardiography revealed an intracardiac mass on the left atrial free wall. Multimodal images from 5 months earlier had shown no mass. We converted the procedure to open surgery. The excised mass resembled a cardiac myxoma but was determined to be a papillary fibroelastoma. This case illustrates that papillary fibroelastomas can form and grow rapidly, warranting alertness for their unexpected discovery before and during cardiac surgical procedures.

Atypical Presentation of Marantic Endocarditis.

We describe a 39-year-old man referred for surgical aortic valve replacement for severe symptomatic aortic stenosis. Intraoperative inspection was unexpectedly consistent with marantic endocarditis. Pathology confirmed nonbacterial thrombotic endocarditis. We present high-resolution intraoperative, diagnostic, and pathology images of nonbacterial thrombotic endocarditis in a patient with antiphospholipid syndrome with atypical presentation.

Extracellular Signal-Regulated Kinase 1 Alone Is Dispensable for Hyperoxia-Mediated Alveolar and Pulmonary Vascular Simplification in Neonatal Mice.

Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveolar and vascular simplification. Hyperoxia, an important BPD causative factor, increases extracellular signal-regulated kinases (ERK)-1/2 expression, whereas decreased lung endothelial cell ERK2 expression reduces angiogenesis and potentiates hyperoxia-mediated BPD in mice. However, ERK1's role in experimental BPD is unclear. Thus, we hypothesized that hyperoxia-induced experimental BPD would be more severe in global ERK1-knockout (ERK1-/-) mice than their wild-type (ERK1+/+ mice) littermates. We determined the extent of lung development, ERK1/2 expression, inflammation, and oxidative stress in ERK1-/- and ERK1+/+ mice exposed to normoxia (FiO2 21%) or hyperoxia (FiO2 70%). We also quantified the extent of angiogenesis and hydrogen peroxide (H2O2) production in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs) with normal and decreased ERK1 signaling. Compared with ERK1+/+ mice, ERK1-/- mice displayed increased pulmonary ERK2 activation upon hyperoxia exposure. However, the extent of hyperoxia-induced inflammation, oxidative stress, and interrupted lung development was similar in ERK1-/- and ERK1+/+ mice. ERK1 knockdown in HPMECs increased ERK2 activation at baseline, but did not affect in vitro angiogenesis and hyperoxia-induced H2O2 production. Thus, we conclude ERK1 is dispensable for hyperoxia-induced experimental BPD due to compensatory ERK2 activation.

Progression of pulmonary veno-occlusive disease without pulmonary hypertension.

Pulmonary veno-occlusive disease (PVOD) is a progressively fatal disease with no definitive treatment options. PVOD can be a result of genetic mutation but can also be due secondary to exposure to solvents or chemotherapeutic agents. Generally, at the time of diagnosis PVOD is associated with hemodynamically confirmed pulmonary hypertension (PH). In this study, we describe a patient who was diagnosed with PVOD early in the disease without hemodynamically confirmed PH. She had histologically confirmed PVOD. Her clinical presentation posed management challenges and prednisone therapy was used to stabilize her disease. This case and some recently published reports highlight possible immune dysregulation in PVOD and role for immuno-suppressive therapy in these patients.

Hidden in Plain Sight: Discovering Giant Cell Aortopathy During Surgical Mitral Valve Repair.

Giant cell arteritis (GCA) is an inflammatory cranial and/or extracranial vasculitis. Although cranial GCA is widely recognized, extracranial GCA is underdiagnosed because of its nonspecific and atypical presentations. We report a case of asymptomatic extracranial GCA with ascending thoracic aortopathy discovered incidentally during surgical mitral valve repair. (Level of Difficulty: Intermediate.).

Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension.

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1-P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

Adrenomedullin Deficiency Potentiates Lipopolysaccharide-Induced Experimental Bronchopulmonary Dysplasia in Neonatal Mice.

Lung inflammation interrupts alveolarization and causes bronchopulmonary dysplasia (BPD). Besides mechanical ventilation and hyperoxia, sepsis contributes to BPD pathogenesis. Adrenomedullin (Adm) is a multifunctional peptide that exerts anti-inflammatory effects in the lungs of adult rodents. Whether Adm mitigates sepsis-induced neonatal lung injury is unknown. The lung phenotype of mice exposed to early postnatal lipopolysaccharide (LPS) was recently shown to be similar to that in human BPD. This model was used to test the hypothesis that Adm-deficient neonatal mice will display increased LPS-induced lung injury than their wild-type (WT) littermates. Adm-deficient mice or their WT littermates were intraperitoneally administered 6 mg/kg of LPS or vehicle daily on postnatal days (PNDs) 3 to 5. The lungs were harvested at several time points to quantify inflammation, alveolarization, and vascularization. The extent of LPS-induced lung inflammation in Adm-deficient mice was 1.6-fold to 10-fold higher than their WT littermates. Strikingly, Adm deficiency induced STAT1 activation and potentiated STAT3 activation in LPS-exposed lungs. The severity of LPS-induced interruption of lung development was also greater in Adm-deficient mice at PND7. At PND14, LPS-exposed WT littermates displayed substantial improvement in lung development, whereas LPS-exposed Adm-deficient mice continued to have decreased lung development. These data indicate that Adm is necessary to decrease lung inflammation and injury and promote repair of the injured lungs in LPS-exposed neonatal mice.

Vancomycin-Associated Tubular Casts and Vancomycin Nephrotoxicity.

INTRODUCTION: Vancomycin nephrotoxicity is frequent and may be due to drug-induced acute tubular necrosis (ATN) or tubulointerstitial nephritis (TIN). Vancomycin-associated tubular cast (VTC) was recently described and may represent a novel cause of vancomycin nephrotoxicity. However, much is still unknown about VTC. MATERIALS AND METHODS: Thirty-seven kidney biopsy specimens from patients who were treated with vancomycin and developed acute kidney injury (AKI) were found among a total of 4673 biopsy samples between 2010 and 2019. These biopsy specimens were subjected to light microscopy, immunofluorescence, electron microscopy, and immunolocalization for vancomycin, uromodulin, myoglobin, tubular segment-specific markers, and examined for VTCs. The findings were correlated with the clinical course. RESULTS: VTCs displayed precipitated vancomycin casts in a background of uromodulin; the casts were limited to the distal tubules, and always associated with a background of more diffuse renal injury (ATN or TIN). The diagnosis of vancomycin nephrotoxicity was made in in 28 of 37 patients. VTC was noted in 25 of 28 biopsy samples from patients diagnosed with vancomycin nephrotoxicity and in one of nine biopsy samples from patients without this diagnosis. Vancomycin nephrotoxicity was diagnosed in 25 of 26 patients whose biopsy specimens showed VTC, but in only 3 of 11 patients without VTC in the biopsy samples. CONCLUSIONS: VTC displays a characteristic morphologic profile amenable to ready recognition in biopsy specimens. It results from coprecipitation of vancomycin and uromodulin. It facilitates the biopsy diagnosis of vancomycin nephrotoxicity. It may have a nephrotoxic effect superimposing on and independent from the ATN or interstitial nephritis in the pathogenesis of vancomycin nephrotoxicity.

A Japanese-American female with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis.

Patients with clinically amyopathic dermatomyositis (CADM) have a risk of developing rapidly progressive interstitial lung disease (ILD). CADM-ILD is associated with the anti-MDA-5 antibody. In the USA, however, patients with CADM have these antibodies less frequently than those in Japan. In addition, those with this disorder are less often complicated with rapidly progressive ILD than those in Japan. We present a case of a 42-year-old Japanese-American female with a 3-month history of a rash on her hands and face with joint pain. Based on the negative results from lupus tests, her primary care provider and a rheumatologist treated her with steroids, hydroxychloroquine, and methotrexate. During treatment, the patient started noticing shortness of breath because of pneumonia, which was revealed by a CT scan. The woman was finally diagnosed with acute respiratory failure due to CADM with ILD. She underwent a double lung transplant as well as treatment with multiple immunosuppressive agents and repeated plasma exchange but died 15 days after transplantation. Her clinical course is similar to that of Japanese patients with CADM-ILD. Outside Japan, primary care providers, rheumatologists, and dermatologists, as well as pulmonary physicians, may be less familiar with this disorder than those in Japan. Since CADM-ILD progresses very quickly and could be fatal, these doctors should be aware of this disease to treat such patients as soon as possible, particularly when seeing a patient of Japanese descent.

Prevalence, Characteristics, and Outcomes of Incidental IgA Glomerular Deposits in Donor Kidneys.

INTRODUCTION: Incidental IgA deposits in donor kidneys have unknown sequelae and may predate clinical kidney disease if primed by adverse immunologic or hemodynamic stimuli or may remain dormant. METHODS: The presence of incidental IgA in post-implantation (T0) biopsies from living (LDK) and deceased donor (DDK) kidneys, and its relationship to post-transplant patient and graft outcomes was investigated in an ethnically diverse US population at a large transplant center. RESULTS: Mesangial IgA was present in 20.4% of 802 T0 biopsies; 13.2% and 24.5% of LDK and DDK, respectively. Donors with incidental IgA deposits were more likely to have hypertension and be of Hispanic or Asian origin. Intensity of IgA staining was 1+ (57.3%), 2+ (26.8%), or 3+ (15.8%) of the T0 IgA+ biopsies. Mesangial pathology correlated with higher-intensity IgA staining with less clearance on follow-up (53.8%) versus 79.2% without mesangial pathology. IgA cleared in 91%, 63%, and 40% of follow-up biopsies with 1+, 2+, and 3+ IgA staining, respectively. Early post-transplant rejection and rejection-related graft loss occurred more frequently in IgA+ kidney recipients; however, 5-year kidney function and graft survival were comparable to kidneys without IgA. CONCLUSION: This first and largest report of incidental IgA in T0 biopsies of LDK and DDK in a US ethnically diverse population demonstrated no adverse association between the presence of IgA in donor kidneys and graft or patient survival. Whether IgA in donor kidneys represents latent IgA nephropathy (IgAN) is uncertain; nevertheless, living donors who demonstrate IgA on T0 biopsy deserve careful follow-up.