Brazilian consortium for the study on renal diseases associated with COVID-19 : a multicentric effort to understand SARS-CoV-2-related nephropathy

Kidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Serviços Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2

Clinical-radiological characterization and treatment of multiple and/or large angiomyolipomas with mTOR inhibitor: effects on the vascular, adipose and muscular components and risk assessment associated with nephrectomy and tumor bleeding

Angiomiolipomas renais (AMLs) são tumores complexos com componentes vascular, gorduroso e muscular. Apresentam prevalência relativamente elevada na população geral, ocorrendo geralmente na forma esporádica. Em cerca de 10% dos casos, entretanto, AMLs associam-se com o complexo esclerose tuberosa (CET). Nesta doença, tais tumores acometem a maior parte dos pacientes e são geralmente múltiplos, bilaterais e precoces. AMLs podem ainda se associar com linfagioleiomiomatose pulmonar esporádica (LAM) e, raramente, se manifestar como lesões múltiplas isoladas. Sua principal complicação é hemorragia, de caráter potencialmente grave. Por essa razão, intervenções invasivas eram até recentemente indicadas para AMLs com alto risco de sangramento. Esses procedimentos, entretanto, associam-se a risco de perda significativa de massa renal funcional. Inibidores de mTOR, por sua vez, apresentam um importante efeito redutor de volume sobre AMLs. Seus efeitos específicos sobre os diferentes componentes tumorais, entretanto, não são conhecidos. Nesse cenário, investigamos os efeitos do sirolimo sobre os diferentes compartimentos do AML, e especificamente sobre as formações aneurismáticas/ectásicas intratumorais. Também analisamos seu papel potencial como terapia neoadjuvante em pacientes com AMLs submetidos a nefrectomia com preservação de massa renal. Analisamos 147 pacientes com AMLs associados a CET, LAM e múltiplos isolados. Observamos índices elevados de hipertensão arterial, albuminúria e malignidade para a idade avaliada na população estudada. Também detectamos associação entre a realização de nefrectomia e menor taxa de filtração glomerular estimada. Nefrectomia total constituiu preditor independente para doença renal crônica estágio 3 ou acima, enquanto nefrectomia parcial foi identificada como preditor independente para ocorrência de hipertensão arterial. Tratamento com sirolimo reduziu o tamanho dos AMLs, efeito que não diferiu entre pacientes com CET, LAM ou AMLs múltiplos isolados. Pacientes pré-tratados com sirolimo e submetidos a nefrectomia apresentaram elevações menores de creatinina sérica que pacientes nefrectomizados não pré-tratados, 48h e 7 meses após o procedimento cirúrgico. Não foram observados eventos adversos graves relacionados a este pré-tratamento. A análise de 23 tumores de pacientes com CET tratados com sirolimo mostrou redução do volume tumoral, um efeito primariamente determinado pela diminuição dos compartimentos com baixo teor de gordura. De fato, baixo teor de gordura mostrou-se um preditor independente de redução de pelo menos 50% do volume de AMLs em resposta a sirolimo. Interessantemente, o volume do compartimento rico em gordura aumentou em resposta ao sirolimo. Nesse cenário, alguns AMLs pobres em gordura evoluíram com lipossubstituição. Observamos também uma diminuição marcante dos compartimentos altamente vascularizados. Em sintonia com esse achado, detectamos redução maciça de formações aneurismáticas/ectásicas intratumorais em resposta ao inibidor de mTOR. Nosso estudo sugere, portanto, que sirolimo exerça uma ação renoprotetora seguindo-se a nefrectomia em pacientes com CET. Nossos achados sugerem, também, que inibidores de mTOR reduzam o risco de sangramento em AMLs, dada sua indução de redução marcante de vascularização e de vasos aneurismáticos/ectásicos intratumorais.Renal angiomyolipomas (AMLs) are complex tumors with vascular, fatty and muscular components. Their prevalence is relatively high in the general population, usually occurring in the sporadic form. In about 10% of cases, however, AMLs are associated with the tuberous sclerosis complex (TSC). In this disease, such tumors affect most patients and are usually multiple, bilateral and early onset. AMLs may also be associated with sporadic pulmonary lymphagioleiomyomathosis (LAM) and, rarely, manifest as multiple isolated lesions. Its main complication is hemorrhage, a potentially serious event. For this reason, invasive interventions were until recently indicated for AMLs with a high risk of bleeding. These procedures, however, are associated with a risk of significant loss of functional renal mass. mTOR inhibitors, in turn, have shown to exert an important volume-reducing effect on AMLs. Its specific effects on the different tumor components, however, are not known. In this scenario, we investigated the effects of sirolimus on the different compartments of the AML, and specifically on intratumoral aneurysmatic/ectatic formations. We also analyzed its potential role as neoadjuvant therapy in patients with AMLs undergoing nephrectomy with preservation of renal mass. We analyzed 147 patients with AMLs associated with TSC, LAM and multiple isolated lesions. We observed high rates of hypertension, albuminuria and malignancy for the assessed age in the analyzed population. We also detected association between nephrectomy and a lower estimated glomerular filtration rate. Total nephrectomy was an independent predictor for chronic kidney disease stages 3 or above, while partial nephrectomy was identified as an independent predictor for the occurrence of hypertension. Treatment with sirolimus reduced the size of AMLs, an effect that did not differ among patients with TSC, LAM and multiple isolated AMLs. Patients pretreated with sirolimus and undergoing nephrectomy had lower serum creatinine elevations than untreated nephrectomized patients, 48 hours and 7 months after the surgical procedure. There were no serious adverse events related to this pretreatment. Analyses of 23 tumors from TSC patients treated with sirolimus showed reduction in tumor volume, an effect primarily determined by decrease of compartments with low fat content. Low fat content, in fact, was shown to be an independent predictor of an at-least-50% reduction in AML volume in response to sirolimus. Interestingly, the fat-rich compartment volume not only did not decrease but increased in response to sirolimus. In this scenario, some low-fat AMLs evolved with liposubstitution. We also observed a marked decrease in highly vascularized compartments. In line with this finding, we detected a massive reduction of intratumor aneurysmal/ectatic formations in response to the mTOR inhibitor. Our study suggests, therefore, that sirolimus exerts a renoprotective action following nephrectomy in patients with TSC. Our findings also suggest that mTOR inhibitors reduce the bleeding risk in AMLs, given their induction of marked reduction in vascularization and intratumoral aneurysmatic/ectatic vessels

Contributions of genetically-modified animal models to the understanding and intervention in autosomal dominant polycystic kidney disease: present and future

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease, representing the fourth cause of end-stage kidney disease. This disorder occurs due to mutations in the PKD1 (Polycystic Kidney Disease 1) or PKD2 (Polycystic Kidney Disease 2) genes, with most of the cases caused by mutations in PKD1. The products of these genes, polycystin-1 (PC1) and polycystin-2 (PC2), are integral membrane glycoproteins that form a complex expressed in the surface of primary apical cilia of several cells, including renal tubular cells. Such proteins are also expressed in other subcellular sites. PC2 functions as a non-selective cation channel with high permeability to calcium, while PC1 is thought to function as a membrane receptor and likely as an adhesion molecule. Since the discovery and characterization of PKD1 and PKD2, the generation of genetically-modified animal models has prompted remarkable advances in the elucidation of ADPKD pathogenesis and identification of potential therapeutic targets. Such animals included knockout, knockin and spatial and temporal conditional knockout models. These progresses allowed the recognition of a complex genetic network involved in the modulation of polycystic kidney disease and the identification of potential modifiers of ADPKD. The mentioned advances also allowed the performance of strategic preclinical studies in mouse models orthologous to this disease, creating appropriate platforms to support robust clinical trials. The generation of composed mutants will likely lead to progressively more complex and specific analyses of ADPKD pathogenesis in the next decades, with meaningful clinical consequences. Moreover, the technical complexity and speed of generating strategic genetically-modified animal models has dramatically improved in recent years, considerably expanding the possibilities for the coming future. In addition, recently developed in vitro approaches such as induced pluripotent stem cells, kidney-on-a-chip and kidney organoid technologies are thought to bring robust and complementary future inputs to the understanding and therapy directed to ADPKD