Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases.

Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Tip Lesion Most Frequent FSGS Variant Related to COVID-19 Vaccine: Two Case Reports and Literature Review.

Large-scale COVID-19 vaccination has been one of the most effective strategies to control the spread of the SARS-CoV-2 virus. However, several cases of glomerular injury related to the COVID-19 vaccine have been described in the literature. We report two cases of a tip lesion variant of focal segmental glomerulosclerosis (FSGS), which presented with significant proteinuria and improved after immunosuppression. In our literature review, the tip lesion variant of FSGS is currently the most frequent variant associated with vaccination against COVID-19. Prognosis is favorable and without significant alterations in the tubulointerstitial or vascular compartments. Adverse effects of vaccines need to be recognized early and will help us to understand the immune and pathological mechanisms of kidney damage.

Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII). / Rivaroxabana em Pacientes Ambulatoriais com COVID-19 Leve ou Moderada: Fundamentação e Desenho do Estudo CARE (CARE ­ Coalition COVID-19 Brazil VIII).

BACKGROUND: Previous studies have demonstrated a high risk of arterial and venous thromboembolic events as a consequence of direct viral damage to endothelial cells by SARS-CoV-2 and a procoagulant milieu due to increased biomarkers, such as D-dimer, fibrinogen, and factor VIII. Although randomized controlled trials of antithrombotic therapies have been conducted in hospitalized patients, few have evaluated the role of thromboprophylaxis in an outpatient setting. OBJECTIVE: To assess whether antithrombotic prophylaxis with rivaroxaban reduces the risk of venous or arterial thrombotic events, invasive ventilatory support, and death in COVID-19 outpatients. METHODS: The COVID Antithrombotic Rivaroxaban Evaluation (CARE) study, a multicenter, randomized, open-label, controlled trial of rivaroxaban 10 mg once daily for 14 days or local standard treatment alone to prevent adverse outcomes, is registered in clinicaltrials.gov (NCT04757857). The inclusion criteria are adults with confirmed or suspected SARS-CoV-2 infection and mild or moderate symptoms without indication for hospitalization, within 7 days of symptom onset, and 1 risk factor for COVID-19 complication (> 65 years, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease or other chronic lung diseases, smoking, immunosuppression, or obesity). The primary composite endpoint, which includes venous thromboembolism, invasive mechanical ventilation, major acute cardiovascular events, and mortality within 30 days of randomization, will be assessed according to the intention-to-treat principle. All patients will provide informed consent. A significance level of 5% will be used for all statistical tests. RESULTS: Major thrombotic and bleeding outcomes, hospitalizations, and deaths will be centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. CONCLUSION: The CARE study will provide relevant and contemporary information about the potential role of thromboprophylaxis in outpatients with COVID-19.

FUNDAMENTO: Estudos anteriores revelaram alto risco de eventos tromboembólicos arteriais e venosos como consequência de danos virais diretos do SARS-CoV-2 em células endoteliais e um meio procoagulante devido ao aumento de biomarcadores como o D-dímero, fibrinogênio, fator VIII. Foram realizados ensaios controlados randomizados de terapias antitrombóticas em pacientes internados, no entanto, poucos estudos avaliaram o papel da tromboprofilaxia no ambiente ambulatorial. OBJETIVO: Avaliar se a profilaxia antitrombótica com rivaroxabana reduz o risco de eventos trombóticos venosos ou arteriais, suporte ventilatório invasivo e morte em pacientes ambulatoriais com COVID-19. MÉTODOS: O estudo CARE é um ensaio randomizado, aberto, multicêntrico e controlado por rivaroxabana 10 mg uma vez por dia durante 14 dias ou tratamento local padrão isolado, para a prevenção de resultados adversos, registrado no Clinicaltrials.gov (NCT04757857). Os critérios de inclusão são adultos com infecção confirmada ou suspeita do SARS-CoV-2, com sintomas leves ou moderados, sem indicação de hospitalização, no prazo de 7 dias após o início dos sintomas e um fator de risco de complicação da COVID-19 (>65 anos, hipertensão, diabetes, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). O desfecho primário composto inclui tromboembolismo venoso, necessidade de ventilação mecânica invasiva, eventos cardiovasculares agudos maiores e mortalidade no prazo de 30 dias após a randomização, sendo avaliado segundo o princípio da intenção de tratar. Todos os pacientes assinaram termo de consentimento. Foi estabelecido um nível de significância de 5% para todos os testes estatísticos. RESULTADOS: Os principais desfechos trombóticos e hemorrágicos, hospitalizações e mortes serão avaliados centralmente por um comitê de eventos clínicos independente, sob a condição cega para a alocação dos grupos de tratamento. CONCLUSÃO: O estudo CARE fornecerá informação relevante e contemporânea sobre o possível papel da tromboprofilaxia em pacientes ambulatoriais com COVID-19.

Primary Effusion Lymphoma: A Rare and Challenging Diagnosis for Recurrent Pleural Effusion.

Primary Effusion Lymphoma is an extremely rare and aggressive subtype of B-cell lymphoma, accounting for only <1% of all cases of this neoplasm. It has a unique clinical presentation because it has a predilection for appearing in body cavities, such as the pleural space, pericardium and peritoneum. It mainly affects immunocompromised individuals and may also affect individuals in the Mediterranean region and in areas endemic for human herpesvirus 8 (HHV-8). Herein, we report the case of an 83-year-old immunocompetent male complaining of coughing, fever and progressive dyspnea for 3 days. His past medical history revealed a recurrent pleural effusion for the last three years, as well as losing weight and malaise. A subsequent investigation revealed a PEL diagnosis of the pleura.

Five-year cardiovascular outcomes in patients with chronic myeloid leukemia treated with imatinib, dasatinib, or nilotinib: A cohort study using data from a large multinational collaborative network.

Background: Breakpoint cluster region-Abelson gene (BCR-ABL) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, concern has arisen about the cardiac safety profile of these drugs. Objectives: This study aims to compare long-term risks of adverse cardiovascular and cerebrovascular events (ACE), heart failure or left ventricular ejection fraction (LVEF) < 50%, and venous thromboembolic events (VTE) in patients with CML treated with BCR-ABL TKIs, using data from a large multinational network. Methods: Patients aged ≥ 18 years with CML treated with imatinib, dasatinib, or nilotinib without prior cardiovascular or cerebrovascular disease were included. We used propensity score matching to balance the cohorts. The 5-year cumulative incidences and hazard ratios were calculated. Results: We identified 3,722 patients with CML under treatment with imatinib (n = 1,906), dasatinib (n = 1,269), and nilotinib (n = 547). Patients with imatinib compared to dasatinib showed a higher hazard ratio (HR) for ACE (HR 2,13, 95% CI 1.15-3.94, p = 0.016). Patients with imatinib presented a lower HR than nilotinib for ACE (HR 0.50, 95% CI 0.30-0.83, p = 0.0074). In relation to heart failure or LVEF < 50%, patients with imatinib had a higher HR than dasatinib (HR 9.41, 95% CI 1.22-72.17, p = 0.03), but no significant difference was observed between imatinib and nilotinib (HR 0.48, 95% CI 0.215-1.01, p = 0.064). Conclusion: In this retrospective study with a large number of patients with CML, those treated with nilotinib had a higher 5-year ratio of ACE, while patients with dasatinib showed a lower ratio than patients with imatinib. The ratio of heart failure was higher in patients with imatinib than in patients with dasatinib, but not when compared to nilotinib.

Rivaroxabana em Pacientes Ambulatoriais com COVID-19 Leve ou Moderada: Fundamentação e Desenho do Estudo CARE (CARE - Coalition COVID-19 Brazil VIII) / Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII)

Resumo Fundamento Estudos anteriores revelaram alto risco de eventos tromboembólicos arteriais e venosos como consequência de danos virais diretos do SARS-CoV-2 em células endoteliais e um meio procoagulante devido ao aumento de biomarcadores como o D-dímero, fibrinogênio, fator VIII. Foram realizados ensaios controlados randomizados de terapias antitrombóticas em pacientes internados, no entanto, poucos estudos avaliaram o papel da tromboprofilaxia no ambiente ambulatorial. Objetivo Avaliar se a profilaxia antitrombótica com rivaroxabana reduz o risco de eventos trombóticos venosos ou arteriais, suporte ventilatório invasivo e morte em pacientes ambulatoriais com COVID-19. Métodos O estudo CARE é um ensaio randomizado, aberto, multicêntrico e controlado por rivaroxabana 10 mg uma vez por dia durante 14 dias ou tratamento local padrão isolado, para a prevenção de resultados adversos, registrado no Clinicaltrials.gov (NCT04757857). Os critérios de inclusão são adultos com infecção confirmada ou suspeita do SARS-CoV-2, com sintomas leves ou moderados, sem indicação de hospitalização, no prazo de 7 dias após o início dos sintomas e um fator de risco de complicação da COVID-19 (>65 anos, hipertensão, diabetes, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). O desfecho primário composto inclui tromboembolismo venoso, necessidade de ventilação mecânica invasiva, eventos cardiovasculares agudos maiores e mortalidade no prazo de 30 dias após a randomização, sendo avaliado segundo o princípio da intenção de tratar. Todos os pacientes assinaram termo de consentimento. Foi estabelecido um nível de significância de 5% para todos os testes estatísticos. Resultados Os principais desfechos trombóticos e hemorrágicos, hospitalizações e mortes serão avaliados centralmente por um comitê de eventos clínicos independente, sob a condição cega para a alocação dos grupos de tratamento. Conclusão O estudo CARE fornecerá informação relevante e contemporânea sobre o possível papel da tromboprofilaxia em pacientes ambulatoriais com COVID-19.

Abstract Background Previous studies have demonstrated a high risk of arterial and venous thromboembolic events as a consequence of direct viral damage to endothelial cells by SARS-CoV-2 and a procoagulant milieu due to increased biomarkers, such as D-dimer, fibrinogen, and factor VIII. Although randomized controlled trials of antithrombotic therapies have been conducted in hospitalized patients, few have evaluated the role of thromboprophylaxis in an outpatient setting. Objective To assess whether antithrombotic prophylaxis with rivaroxaban reduces the risk of venous or arterial thrombotic events, invasive ventilatory support, and death in COVID-19 outpatients. Methods The COVID Antithrombotic Rivaroxaban Evaluation (CARE) study, a multicenter, randomized, open-label, controlled trial of rivaroxaban 10 mg once daily for 14 days or local standard treatment alone to prevent adverse outcomes, is registered in clinicaltrials.gov (NCT04757857). The inclusion criteria are adults with confirmed or suspected SARS-CoV-2 infection and mild or moderate symptoms without indication for hospitalization, within 7 days of symptom onset, and 1 risk factor for COVID-19 complication (> 65 years, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease or other chronic lung diseases, smoking, immunosuppression, or obesity). The primary composite endpoint, which includes venous thromboembolism, invasive mechanical ventilation, major acute cardiovascular events, and mortality within 30 days of randomization, will be assessed according to the intention-to-treat principle. All patients will provide informed consent. A significance level of 5% will be used for all statistical tests. Results Major thrombotic and bleeding outcomes, hospitalizations, and deaths will be centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. Conclusion The CARE study will provide relevant and contemporary information about the potential role of thromboprophylaxis in outpatients with COVID-19.

Kidney injury associated with COVID-19 infection and vaccine: A narrative review.

The respiratory tract is the main infection site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in many admissions to intensive care centers in several countries. However, in addition to lung involvement, kidney injury caused by the novel coronavirus has proven to be a significant factor related to high morbidity and mortality, alarming experts worldwide. The number of deaths has drastically reduced with the advent of large-scale immunization, highlighting the importance of vaccination as the best way to combat the pandemic. Despite the undeniable efficacy of the vaccine, the renal side effects associated with its use deserve to be highlighted, especially the emergence or reactivation of glomerulopathies mentioned in some case reports. This study aimed to identify the main renal morphological findings correlated with COVID-19 infection and its vaccination, seeking to understand the pathophysiological mechanisms, main clinical features, and outcomes.

Systemic amyloidosis journey from diagnosis to outcomes: a twelve-year real-world experience of a single center in a middle-income country.

BACKGROUND: Systemic amyloidosis is caused by the deposition of misfolded protein aggregates in tissues, leading to progressive organ dysfunction and death. Epidemiological studies originate predominantly from high-income countries, with few data from Latin America. Due to the non-specific clinical manifestations, diagnosing amyloidosis is often challenging and patients experience a long journey and delay in diagnosis. This study aimed to assess clinical and laboratory characteristics, the diagnostic journey, and outcomes of patients with biopsy-proven systemic amyloidosis diagnosed between 2009 and 2020 at a university referral center in a middle-income Latin American country. Patients´ medical records were retrospectively reviewed. RESULTS: One hundred and forty-three patients were included. The median age at diagnosis was 60 years and 54% were male. Until the diagnosis, most of the patients (52%) were seen by at least 3 specialists, the main ones being: general practitioners (57%), nephrologists (45%), and cardiologists (38%). The most common manifestations were renal (54%) and cardiac (41%) disorders, and cachexia was seen in 36% of patients. In 72% of the cases, ≥ 2 biopsies were required until the final diagnosis. The median time from symptoms onset to diagnosis was 10.9 months, and most patients (75%) had ≥ 2 organs involved. The following subtypes were identified: AL (68%), ATTR (13%), AA (8%), AFib (4%), and inconclusive (7%). Median OS was 74.3 months in the non-AL subgroup and 18.5 months in AL. Among AL patients, those with advanced cardiac stage had the worst outcome [median OS 8.6 months versus 52.3 for stage III versus I-II, respectively (p < 0.001)]. AL subtype, cardiac involvement, and ECOG ≥ 2 were identified as independent risk factors for reduced survival. CONCLUSIONS: Systemic amyloidosis is still an underdiagnosed condition and the delay in its recognition leads to poor outcomes. Medical education, better diagnostic tools, improvement in access to therapies, and establishment of referral centers may improve patient outcomes in middle-income countries.

Dialysis-related constrictive pericarditis: old enemies may sometimes come back / Pericardite Constritiva relacionada a diálise: velhos inimigos podem, às vezes, voltar

ABSTRACT Cardiovascular disease is the main cause of death in patients with chronic kidney disease (CKD). Several heart conditions have been associated with CKD, including myocardial and pericardial diseases. This paper describes a case of Dialysis-related constrictive pericarditis in a patient diagnosed with sudden hypotension during a hemodialysis session. A 65-year-old man diagnosed with hypertension, diabetes, obesity, and cirrhosis on hemodialysis for two years complained of symptoms during one of his sessions described as malaise, lipothymia, and confusion. The patient had a record of poor compliance with the prescribed diet and missed dialysis sessions. He was sluggish during the physical examination, and presented hypophonetic heart sounds, a blood pressure of 50/30mmHg, and a prolonged capillary refill time. The patient was referred to the intensive care unit and was started on antibiotics and vasoactive drugs. His workup did not show signs of infection, while electrocardiography showed low QRS-wave voltage. His echocardiogram showed signs consistent with a thickened pericardium without pericardial effusion. Cardiac catheterization showed equalization of diastolic pressures in all heart chambers indicative of constrictive pericarditis. The patient underwent a pericardiectomy. Examination of surgical specimens indicated he had marked fibrosis and areas of dystrophic calcification without evidence of infection, consistent with Dialysis-related constrictive pericarditis. Hypotension for unknown causes must be considered in the differential diagnosis of dialysis patients.

RESUMO A doença cardiovascular é a principal causa de morte em pacientes com doença renal crônica (DRC). Várias formas de acometimento cardíaco têm sido associadas. à DRC, incluindo doenças miocárdicas e pericárdicas. Este artigo descreve um caso de pericardite constritiva relacionada a em um paciente diagnosticado com hipotensão súbita durante uma sessão de hemodiálise. Um homem de 65 anos com diagnósticos prévios de hipertensão, diabetes, obesidade e cirrose em hemodiálise por dois anos queixou-se de sintomas durante uma de suas sessões, descritos como mal-estar, lipotímia e confusão mental. Apresentava histórico de baixa adesão à dieta prescrita e faltas frequentes às sessões de diálise. Ele estava fraco durante o exame físico e apresentava bulhas cardíacas hipofonéticas, pressão arterial de 50/30mmHg e tempo de enchimento capilar prolongado. O paciente foi encaminhado para a unidade de terapia intensiva e iniciou o tratamento com antibióticos e drogas vasoativas. Investigação laboratorial não mostrou sinais de infecção, enquanto o eletrocardiograma mostrou baixa voltagem de complexo QRS. Seu ecocardiograma evidenciou sinais consistentes com um pericárdio espessado, sem derrame pericárdico. O cateterismo cardíaco mostrou equalização das pressões diastólicas em todas as câmaras cardíacas, indicativo de pericardite constritiva. O paciente foi submetido a uma pericardiectomia. O exame anatomopatológico mostrou sinais de acentuada fibrose acentuada fibrose e áreas de calcificação distrófica sem evidência de infecção, consistente com pericardite constritiva relacionada a por diálise. A hipotensão por causas desconhecidas deve ser considerada no diagnóstico diferencial de pacientes em diálise.

Membranous Nephropathy Secondary to Graves' Disease: A Case Report.

Membranous nephropathy (MN) is a form of kidney disease that is idiopathic in 70%-80% of cases. Glomerular involvement in autoimmune thyroiditis can occur in 10%-30% of patients, and MN manifests in association with Hashimoto thyroiditis in up to 20% of the cases with glomerular involvement. Reports of MN associated with Graves' disease (GD) are extremely rare in the current literature. Herein, we report the case of a 46-year-old man admitted to the hospital with nephrotic syndrome and symptomatic hyperthyroidism due to GD. Kidney biopsy revealed a secondary MN pattern. Immunohistochemical staining for PLA2R was negative, and thyroglobulin showed weak and segmental staining along the glomerular capillary. Anti-thyroid peroxidase (TPO) antibody test was not performed. The patient was treated for GD with methimazole and prednisone, and despite reaching clinical improvement after 8 months, proteinuria remained close to nephrotic levels. In this scenario, the patient was submitted to radioactive iodine, and there was a dramatic reduction in proteinuria levels after treatment. In conclusion, GD association with MN is rare, and when present, diagnosis using PLA2R and immunohistochemistry can be useful in determining association. In addition, radioactive iodine therapy can be an effective treatment modality when preceded with immunosuppressive corticosteroid therapy.

Collapsing Glomerulopathy: A Review by the Collapsing Brazilian Consortium.

Collapsing glomerulopathy (CG) is a clinicopathologic entity characterized by segmentar or global collapse of the glomerulus and hypertrophy and hyperplasia of podocytes. The Columbia classification of 2004 classified CG as a histological subtype of focal segmental glomerulosclerosis (FSGS). A growing number of studies have demonstrated a high prevalence of CG in many countries, especially among populations with a higher proportion of people with African descent. The present study is a narrative review of articles extracted from PubMed, Medline, and Scielo databases from September 1, 2020 to December 31, 2021. We have focused on populational studies (specially cross-sectional and cohort articles). CG is defined as a podocytopathy with a distinct pathogenesis characterized by strong podocyte proliferative activity. The most significant risk factors for CG include APOL1 gene mutations and infections with human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2. CG typically presents with more severe symptoms and greater renal damage. The prognosis is notably worse than that of other FSGS subtypes.

Chikungunya virus as a trigger for different renal disorders: an exploratory study.

INTRODUCTION: Chikungunya virus was detected in cases of acute chikungunya fever in renal tissue. However, chikungunya virus-related kidney injury still lacks characterization, and it is unknown whether the kidneys are reservoirs for the virus. We sought to detect histopathological changes and viral antigens in renal tissue, and to evaluate kidney injury markers in different phases of chikungunya fever. METHODS: Two groups were evaluated in this exploratory study: patients with biopsy-proven kidney injury established after chikungunya fever, and patients with post-chikungunya fever chronic joint manifestations without known kidney injury, in whom we actively searched for kidney injury markers. RESULTS: In the first group, 15 patients had kidney injury 0.5-24 months after chikungunya fever. The most frequent histopathological diagnoses were glomerular lesions. No viral antigens were detected in renal tissue. High-risk genotypes were detected in patients with atypical hemolytic uremic syndrome and focal and segmental glomerulosclerosis. In the second group, 114 patients had post-chikungunya fever joint manifestations on average for 35.6 months. Mean creatinine and proteinuria were 0.9 mg/dl and 71.5 mg/day, respectively. One patient had isolated hematuria. There was no indication for renal biopsy in this group. CONCLUSIONS: Several histopathological features were found after chikungunya fever, without virus detection in renal tissue. These findings suggest that chikungunya virus may trigger kidney lesions with varying degrees of severity at different stages of infection. However, the probability that this virus replicates in the renal tissue seems unlikely.

Thrombotic microangiopathy associated with arboviral infection: Report of 3 cases.

Dengue fever and chikungunya are viral diseases that have spread rapidly throughout the world in recent decades. The occurrence of complications is well known, including prerenal acute kidney injury (AKI), which is usually thought to be caused by dehydration and fluid loss. Thrombotic microangiopathy (TMA) is an uncommon aggravation of dengue fever and chikungunya, with only a few cases described in the medical literature. The aim of this study is to present 3 cases of TMA associated with arboviral infection. Three patients with clinical history, laboratory test, and kidney biopsy results compatible with TMA were selected for the study, 2 of whom had a serological diagnosis of dengue fever and 1 of chikungunya. The 3 patients were followed up at the Federal University of Maranhão Hospital's Nephrology Service in 2018. A targeted gene panel sequencing (TGPS) plus multiple to atypical hemolytic uremic syndrome (aHUS) multiplex ligation-dependent probe amplification (MLPA) was performed in 2 of the patients and revealed in the patient 1 a heterozygous pathogenic variant in the gene THBD, as well as heterozygous deletions in CFH, CFHR1, and CFHR3. In the patient 2, there were heterozygous pathogenic variant in the genes CFI and CFB, in addition to heterozygous deletions in the genes CFHR1 and CFHR3. Both received treatment with eculizumab and undergone recovery of renal function. The third patient had TMA not classified as either aHUS or thrombotic thrombocytopenic purpura (TTP); he abandoned the treatment and returned to the service after 2 years for a dialysis emergency. Patients with arboviral infectious disease and changes that suggest TMA should have appropriate support to establish early diagnosis and useful treatment.

Methimazole-Induced ANCA Vasculitis: A Case Report.

Rapidly progressive glomerulonephritis (RPGN) is a syndrome which presents rapid loss of renal function. Vasculitis represents one of the major causes, often related to anti-neutrophil cytoplasmic antibodies (ANCA). Herein, we report a case of methimazole-induced ANCA-associated vasculitis. A 35-year-old woman complained of weight loss and fatigue for 2 weeks and attended the emergency room with alveolar hemorrhage. She had been diagnosed with Graves' disease and had been taking methimazole in the past 6 months. Her physical examination showed pulmonary wheezing, hypertension and signs of respiratory failure. Laboratory tests revealed urea 72 mg/dL, creatinine 2.65 mg/dL (eGFR CKD-EPI: 20 mL/min/1.73 m2), urine analysis with >100 red blood cells per high-power field, 24 h-proteinuria: 1.3 g, hemoglobin 6.6 g/dL, white-cell count 7700/mm3, platelets 238,000/mm3, complement within the normal range, negative viral serological tests and ANCA positive 1:80 myeloperoxidase pattern. Chest tomography showed bilateral and diffuse ground-glass opacities, and bronchial washing confirming alveolar hemorrhage. A renal biopsy using light microscopy identified 27 glomeruli (11 with cellular crescentic lesions), focal disruption in glomerular basement membrane and fibrinoid necrosis areas, tubulitis and mild interstitial fibrosis. Immunofluorescence microscopy showed IgG +2/+3, C3 +3/+3 and Fibrinogen +3/+3 in fibrinoid necrosis sites. She was subsequently diagnosed with crescentic pauci-immune glomerulonephritis, mixed class, in the setting of a methimazole-induced ANCA vasculitis. The patient was treated with methimazole withdrawal and immunosuppressed with steroids and cyclophosphamide. Four years after the initial diagnosis, she is currently being treated with azathioprine, and her exams show creatinine 1.30 mg/dL (eGFR CKD-EPI: 52 mL/min/1.73 m2) and negative p-ANCA.

Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E. LPG mainly affects Asian individuals, however occasional cases have also been described in Americans and Europeans. Herein we report two unrelated Brazilian patients with LPG in whom genetic analyses revealed the APOE-Osaka/Kurashiki variant. CASE PRESENTATION - CASE 1: A 29-year-old Caucasian male sought medical attention with complaints of face swelling and foamy urine for the last 3 months. He denied a family history of kidney disease, consanguinity, or Asian ancestry. His tests showed proteinuria of 12.5 g/24 h, hematuria, serum creatinine 0.94 mg/dL, albumin 2.3 g/dl, total cholesterol 284 mg/dL, LDL 200 mg/dL, triglycerides 175 mg/dL, and negative screening for secondary causes of glomerulopathy. A kidney biopsy revealed intraluminal, laminated deposits of hyaline material in glomerular capillaries consistent with lipoprotein thrombi. These findings were confirmed by electron microscopy, establishing the diagnosis of LPG. His apolipoprotein E serum level was 72 mg/dL and genetic analysis revealed the APOE pathogenic variant c.527G > C, p.Arg176Pro in heterozygosis, known as the Osaka/Kurashiki mutation and positioned nearby the LDL receptor binding site. CASE 2: A 34-year-old Caucasian man sought medical assessment for renal dysfunction and hypertension. He reported intermittent episodes of lower-limb edema for 3 years and a family history of kidney disease, but denied Asian ancestry. Laboratorial tests showed BUN 99 mg/dL, creatinine 10.7 mg/dL, total cholesterol 155 mg/dL, LDL 79 mg/dL, triglycerides 277 mg/dL, albumin 3.1 g/dL, proteinuria 2.7 g/24 h, and negative screening for secondary causes of glomerulopathy. His kidney biopsy was consistent with advanced chronic nephropathy secondary to LPG. A genetic analysis also revealed the Osaka/Kurashiki variant. He was transplanted a year ago, displaying no signs of disease relapse. CONCLUSION: We report two unrelated cases of Brazilian patients with a diagnosis of lipoprotein glomerulopathy whose genetic assessment identified the APOE-Osaka/Kurashiki pathogenic variant, previously only described in eastern Asians. While this is the second report of LPG in Latin America, the identification of two unrelated cases by our medical team raises the possibility that LPG may be less rare in this part of the world than currently thought, and should definitely be considered when nephrotic syndrome is associated with suggestive kidney biopsy findings.

The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures.

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses.

BACKGROUND: APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. METHODS: Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. RESULTS: Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. CONCLUSIONS: Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.

Renal thrombotic microangiopathy associated to worse renal prognosis in Lupus Nephritis.

INTRODUCTION: Renal thrombotic microangiopathy (rTMA) is one of many vascular findings in Lupus Nephritis (LN). However, the influence of rTMA on prognosis has not been well established. The objective of this study was to evaluate the clinical and pathological aspects of patients with lupus and rTMA in kidney biopsy. METHODS: Analysis of medical reports and kidney biopsy of 253 patients with LN, between January 2012 and December 2018. RESULTS: Among our 253 patients, 43 (17%) showed acute or chronic TMA lesions on kidney histology This group had a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (24.1 vs. 64.15 ml/min/1.73m2, p < 0.001), at 1 year of follow up (28.1 vs. 90.7 ml/min/1.73m2, p < 0.001), and at the end of follow up (25.4 vs. 81.55 ml/min/1.73m2, p < 0.001). More patients in the rTMA group reached the composite endpoint of eGFR < 15 mL/min/1.73m2 or death or dialysis (82.9% vs. 32.9%, p < 0.001). When comparing the classical clinical TMA features, the rTMA group had higher percentages of anemia, thrombocytopenia, low haptoglobin levels, but not higher lactate dehydrogenase (LDH) levels (> 214 U/L). Combining these variables in a definition of clinical TMA, the rTMA group had a statistically higher percentage of clinical TMA (20.9% vs. 4.33%, p = 0.001). As expected, TMA group showed higher systolic blood pressure (SBP) (130 vs 129.5 mmHg, p = 0.01). Concerning histopathological features, rTMA group had significantly higher activity (9.0 vs. 6.0, p = 0.001) and chronicity (4.0 vs. 3.0, p = 0.001) scores, also a higher percentage of patients presented with crescents (76.7% vs. 57.1%, p = 0.012). CONCLUSIONS: The classical clinical TMA criteria were unable to predict the presence of tissue TMA, suggesting a probably renal-limited TMA that may occur independently of systemic evident factors. Therefore, renal biopsy remains the critical method for diagnosing an important prognostic feature.

Evidences of histologic thrombotic microangiopathy and the impact in renal outcomes of patients with IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is the most common primary glomerulopathy worldwide. According to the Oxford Classification, changes in the kidney vascular compartment are not related with worse outcomes. This paper aims to assess the impact of thrombotic microangiopathy (TMA) in the outcomes of Brazilian patients with IgAN. MATERIALS AND METHODS: Analysis of clinical data and kidney biopsy findings from patients with IgAN to assess the impact of TMA on renal outcomes. RESULTS: The majority of the 118 patients included were females (54.3%); mean age of 33 years (25;43); hypertension and hematuria were observed in 67.8% and 89.8%, respectively. Median creatinine: 1.45mg/dL; eGFR: 48.8ml/min/1.73m2; 24-hour proteinuria: 2.01g; low serum C3: 12.5%. Regarding to Oxford Classification: M1: 76.3%; E1: 35.6%; S1: 70.3%; T1/T2: 38.3%; C1/C2: 28.8%. Average follow-up: 65 months. Histologic evidence of TMA were detected in 21 (17.8%) patients and those ones presented more frequently hypertension (100% vs. 61%, p <0.0001), hematuria (100% vs 87.6%, p = 0.0001), worse creatinine levels (3.8 vs. 1.38 mg/dL, p = 0.0001), eGFR (18 vs. 60 ml/min/1.73m2), p = 0.0001), low serum C3 (28.5% vs. 10.4%, p = 0.003), lower hemoglobin levels (10.6 vs. 12.7g/dL, p<0.001) and platelet counts (207,000 vs. 267,000, p = 0.001). Biopsy findings of individuals with TMA revealed only greater proportions of E1 (68% vs. 32%, p = 0.002). Individuals with TMA were followed for less time (7 vs. 65 months, p<0.0001) since they progressed more frequently to chronic kidney disease (CKD) requiring kidney replacement therapy (KRT) (71.4% vs. 21,6%, p<0.0001). Male sex, T1/T2, and TMA were independently associated with progression to CKD-KRT. CONCLUSIONS: In this study patients with TMA had worse clinical manifestations and outcomes. In terms of histologic evidence, E1 distinguished patients with TMA from other patients. Further studies are necessary to analyze the impact of vascular lesions on IgAN prognosis.

An elderly diabetic patient with McArdle disease and recurrent rhabdomyolysis: a potential association with late hypoinsulinemia?

BACKGROUND: McArdle disease is a myopathy caused by mutations in PYGM gene that is characterized by reduced or absent activity of myophosphorylase. Reports of patients with concomitant McArdle disease and diabetes are scarce. We report a case of a patient with a late diagnosis of McArdle disease and we postulate that symptoms may be related to hypoinsulinemia. CASE PRESENTATION: This report describes the evolution of an elderly diabetic patient with confirmed diagnosis of McArdle's disease based on the absence of myophosphorylase activity in the analysis of muscle biopsy, and a homozygous mutation in the PYGM gene. The variant - Chr11: 64.525 (p. Asn168*fs) has not been previously described. The diagnosis of McArdle disease was confirmed after two episodes of rhabdomyolysis, at 77 and 81 years of age, as the symptoms were, until then, discrete. The "second-wind phenomenon" was not spontaneously reported, but it was confirmed when directly questioned. We postulate that the later episodes of rhabdomyolysis occurred because of a progressive decrease in insulin production with a consequent reduction in the uptake of blood glucose by muscle cells, thus compromising the cellular energy balance. To our knowledge, this is the first report of recurrent rhabdomyolysis in an elderly diabetic patient with genetically proven McArdle disease. Our initial attempt to reduce insulin resistance with metformin and pioglitazone was not effective, possibly because of inadequate insulinemia. However, an improvement was evident after the administration of low doses of intermediate-acting insulin. CONCLUSIONS: In view of the patient's clinical evolution, we suggest the use of medication that reduces insulin resistance for patients with McArdle disease and type 2 diabetes, pre-diabetes or even normoglycemic metabolic syndrome.