A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo

The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test prospective therapies in vivo. Generation of kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs allows us to recapitulate a rare kidney tumor called angiomyolipoma (AML). Organoids derived from TSC2−/− hiPSCs but not from isogenic TSC2+/− or TSC2+/+ hiPSCs share a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and develop epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be consistently recapitulated with transgenic mice. Transplantation of multiple TSC2−/− renal organoids into the kidneys of immunodeficient rats allows us to model AML in vivo for the study of tumor mechanisms, and to test the efficacy of rapamycin-loaded nanoparticles as an approach to rapidly ablate AMLs. Collectively, our experimental approaches represent an innovative and scalable tissue-bioengineering strategy for modeling rare kidney disease in vivo.

Digital Spatial Profiling of Collapsing Glomerulopathy

ABSTRACTCollapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV and SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli from HIV and SARS-CoV-2 infected patients with biopsy confirmed collapsing glomerulopathy. The increased resolution of DSP uncovered heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Therefore, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

Predictivity of Antemortem Findings on Postmortem Inspection in Italian Heavy Pigs Slaughterhouses

Pigs slaughtered in European abattoirs must be submitted to antemortem inspection (AMI) and postmortem inspection (PMI), as required by the current European legislation in the matter of official controls. AMI and PMI are equally essential to guarantee food safety and to monitor swine health and welfare. However, little is known about the ability of AMI to predict conditions that are possibly found during PMI. In this study, such a correlation was explored together with the assessment of conditions typically found during AMI and PMI in heavy pigs slaughtered in two Italian slaughterhouses. An assessment scheme containing 13 variables for AMI and 34 lesions for PMI was used for the scope. The herd size was also considered as a variable and included in the study. A total of 24,510 pigs and 30,961 pigs were assessed during AMI and PMI, respectively. The most common conditions found were manure on the body covering more than 30% of the body (dirt >30%) and pluck lesions (‘pleurisy’, ‘pericarditis’, and ‘pneumonia’) for AMI and PMI, respectively. A significant correlation (p < 0.05) between some antemortem (AM) findings and postmortem (PM) conditions was found. In particular, the AM conditions ‘dirt >30%’and ‘skin lesions’ were positively related with PM conditions ‘skin wounds’ and ‘dermatitis’, while the complexes of respiratory and kidney lesions were predicted only by the condition ‘dirt >30%’. The variable ‘standardized herd size’ was negatively associated with ‘milk spot liver’ and positively associated with ‘arthritis/bursitis’. The results of this study show that findings reported during AMI can potentially be used to predict certain conditions found in pigs at PMI. These data can be useful for the competent authorities in characterizing swine farms using a risk-based approach and in developing systems and specific plans for official controls.

Proceedings of the 2020 Classic Examples in Toxicologic Pathology XXVII

The histopathology slide seminar “Classic Examples in Toxicologic Pathology XXVII” was held on February 21 and 22, 2020, at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, with joint organization by the European Society of Toxicologic Pathology. The goal of this annual seminar is to present and discuss classical and actual cases of toxicologic pathology. This article summarizes the presentations given during the seminar, including images of representative lesions. Ten actual and classical cases of toxicologic pathology, mostly induced by a test article, were presented. These included small intestine pathology and transcriptomics induced by a γ-secretase modulator, liver findings in nonhuman primates induced by gene therapy, drug-induced neutropenia in dogs, device-induced growth plate lesions, polycystic lesions in CAR/PXR double knockout mice, inner ear lesions in transgenic mice, findings in Beagle dogs induced by an inhibitor of the myeloid leukemia cell differentiation protein MCL1, findings induced by a monovalent fibroblast growth factor receptor 1 antagonist, kidney lesions induced by a mammalian target of rapamycin inhibitor in combination therapy, and findings in mutation-specific drugs.

Retrospective evaluation of our percutaneous biopsy results of renal masses

Objective: In this study, we aim to present the retrospective results of percutaneous biopsies performed on solid kidney lesions in our clinic with the literature. Materials and Methods: In this retrospective descriptive study approved by the ethics committee in our center, the demographic features and histopathological results of 57 patients who had a solid mass in the kidney between 2017-2020 and underwent ultrasonography-guided percutaneous kidney biopsy in our interventional radiology clinic were analyzed from the hospital database. Patients without pathology results were excluded from the study. Results: Our patients consisted of 35 men (61,4%) and 23 women (38,6%). The average age was 59.02±15.33(6-94). We had 1 child and 56 adult patients. 29 of the kidney lesions were located in the left kidney(50,9%) and 28 were located in the right kidney(49,1%). In 44 patients(77.2%) who had malignant pathology; the results were 41 renal cell carcinoma(93.2%), 2 lung squamous cell carcinoma metastasis(4.5%) and 1 primary metastatic pleomorphic adenoma of the salivary gland(2.3%). In a total of 13 patients(22.8%) whose pathology results were benign; the results were 5 oncocytomas(38.5%), 5 angiomyolipoma(38.5%), 2 chronic pyelonephritis(15.4%) and 1 metanephric adenoma(7.6%). Renal cell carcinoma rate was 71.9% among all lesions. Conclusion: Radiological methods may not provide sufficient diagnostic data in the differential diagnosis of solid renal masses.In our study, the rates of benign lesions as a result of percutaneous biopsy were higher compared to the literature. Therefore, we believe that it is remarkable in terms of the importance of preoperative biopsy in solid lesions. Keywords: renal mass, percutaneous biopsy, renal cell carcinoma

Dysproteinemia-Associated Kidney Diseases: Clinicopathological Correlations

Introduction: Dysproteinemia-associated kidney diseases can have diverse clinical and histological presentation but not all patients with monoclonal gammopathy have Monoclonal Gammopathy of Renal Significance (MGRS) and some have other causes for kidney lesions. Therefore, kidney biopsy is essential to make this diagnosis. We made a retrospective study, which aimed to: 1. Identify dysproteinemiaassociated kidney lesions; 2. Establish clinicopathological correlations of patients with those lesions and 3. Identify kidney and patient survival predictors. Methods: A retrospective, observational chart review of kidney biopsies performed, between January 2015 and February 2020, in three Portuguese Hospitals, to a total of 39 patients, with kidney lesions associated with monoclonal gammopathy, was undertaken. Results: The three main dysproteinemic kidney diseases identified were cast nephropathy, AL amyloidosis and Monoclonal Immunoglobulin Deposition Disease (MIDD), with different features among them. Only three patients fulfilled the criteria to Monoclonal Gammopathy of Renal Significance (MGRS). In regard to treatment, we verified that most of our patients were treated with chemotherapy. Unfortunately, only four recovered, either partially or completely. The mean kidney survival since kidney biopsy was 29,23 months and the mean patient survival since diagnosis was 24,46 months. Some clinical and pathologic features correlated to lowerkidney survival: acute tubular necrosis, cast nephropathy, Thrombotic Microangiopathy (TMA), haemoglobin and estimated Glomerular Filtration Rate (eGFR). Previous Nephrology follow-up correlated with higher kidney survival. Only eGFR was associated with lowerpatient survival.