RESUMO
Mendelian randomization (MR) has become a popular tool for inferring causality of risk factors on disease. There are currently over 45 different methods available to perform MR, reflecting this extremely active research area. It would be desirable to have a standard simulation environment to objectively evaluate the existing and future methods. We present simmrd, an open-source software for performing simulations to evaluate the performance of MR methods in a range of scenarios encountered in practice. Researchers can directly modify the simmrd source code so that the research community may arrive at a widely accepted framework for researchers to evaluate the performance of different MR methods.
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Análise da Randomização Mendeliana , Modelos Genéticos , Humanos , Análise da Randomização Mendeliana/métodos , Variação Genética , Fatores de Risco , CausalidadeRESUMO
BACKGROUND: Membranous-like glomerulopathy with masked monoclonal IgG deposits (MGMID) is a newly recognized condition predominantly observed in young females, and its understanding in the pediatric population remains limited. MATERIALS AND METHODS: Four cases of MGMID are reported, including three pediatric patients. RESULTS: All patients were female, with ages ranging from 12 to 26 years. None of the patients had malignancies. They presented with kidney dysfunction, proteinuria, or hematuria. Kidney biopsies of all cases exhibited a membranous pattern of injury with monoclonal IgG-κ restriction, "unmasked" by pronase digestion. Pediatric cases were treated conservatively, while the adult case underwent immunosuppressive treatment. All patients had favorable outcomes, and none reached end stage kidney disease (ESKD). CONCLUSION: MGMID can affect both adult and pediatric patients. Further studies are needed to fully characterize its risk factors, optimal therapy, and outcomes.
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Glomerulonefrite Membranosa , Imunoglobulina G , Humanos , Feminino , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/complicações , Criança , Adulto , Adolescente , Adulto Jovem , Biópsia , Imunossupressores/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.
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Injúria Renal Aguda/patologia , Betacoronavirus , Infecções por Coronavirus/complicações , Rim/patologia , Pneumonia Viral/complicações , Idoso , Biópsia , COVID-19 , Infecções por Coronavirus/patologia , Feminino , Humanos , Rim/ultraestrutura , Necrose Tubular Aguda/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , SARS-CoV-2RESUMO
BACKGROUND: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized. METHODS: Northwell Health Laboratories tested 46â 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization. RESULTS: From 8 March through 10 April, a total of 26â 735 of 46â 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income. CONCLUSIONS: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.
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COVID-19 , SARS-CoV-2 , Adulto , Feminino , Hospitalização , Humanos , Incidência , Masculino , New YorkRESUMO
AIMS: We aim to describe the clinical and histological findings in patients with the finding of any tubular oxalate deposits in kidney biopsy specimens. BACKGROUND: The prevalence, manifestation, and outcome of secondary oxalate nephropathy have not been extensively studied. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed the clinical and histological findings in all patients with the finding of any tubular oxalate deposits in kidney biopsy specimens between July 1, 2017, and December 31, 2018, at Northwell Health Pathology Department (Manhasset, NY, USA). RESULTS: The prevalence of oxalate deposition on a kidney biopsy was 4.07% (25/615), and in 88% of cases was a major finding. Prior to biopsy, oxalate was anticipated in only 1 case. The etiology of oxalosis was clarified retrospectively in 14 cases, most commonly due to GI surgery (n = 10) and increased oxalate intake (n = 4). In 11 cases, etiology remained unknown, although at least 3 cases were exposed to antibiotics associated with secondary oxalosis. There was no significant clinical/pathological or survival difference between known vs. unknown cause groups. The overall 3-month renal survival rate was 76.0 ± 8.5%. Multivariate Cox regression showed that creatinine at the time of biopsy (HR: 1.79, 95% CI: 0.71 - 4.51), background histological chronicity change (HR: 1.82, 95% CI: 0.70 - 4.72) and oxalate density (HR: 2.27, 95% CI: 0.49 - 10.55) are associated with end-stage kidney disease. CONCLUSION: Oxalate deposition is common but rarely anticipated biopsy finding. Nephrologists need to consider surgical history and other secondary causes of oxalosis as causes of acute kidney injury and chronic kidney disease.
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Rim/metabolismo , Rim/patologia , Oxalatos/metabolismo , Idoso , Biópsia , Cristalização , Feminino , Humanos , Hiperoxalúria/complicações , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.
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Terapia Biológica/métodos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Clostridium/metabolismo , Meios de Contraste/administração & dosagem , Compostos Férricos/administração & dosagem , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/terapia , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/administração & dosagem , Imagem Molecular/métodos , Esporos Bacterianos , Animais , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Clostridium/genética , Clostridium/patogenicidade , Meios de Contraste/metabolismo , Compostos Férricos/metabolismo , Neoplasias Hepáticas Experimentais/microbiologia , Neoplasias Hepáticas Experimentais/patologia , Valor Preditivo dos Testes , Coelhos , Ratos Sprague-DawleyRESUMO
Purpose To demonstrate that anti-MG1 conjugated hybrid magnetic gold nanoparticles (HNPs) act as a catalyst during photothermal ablation (PTA) of colorectal liver metastases, and thus increase ablation zones. Materials and Methods All experiments were performed with approval of the institutional animal care and use committee. Therapeutic and diagnostic multifunctional HNPs conjugated with anti-MG1 monoclonal antibodies were synthesized, and the coupling efficiency was determined. Livers of 19 Wistar rats were implanted with 5 × 106 rat colorectal liver metastasis cell line cells. The rats were divided into three groups according to injection: anti-MG1-coupled HNPs (n = 6), HNPs only (n = 6), and cells only (control group, n = 7). Voxel-wise R2 and R2* magnetic resonance (MR) imaging measurements were obtained before, immediately after, and 24 hours after injection. PTA was then performed with a fiber-coupled near-infrared (808 nm) diode laser with laser power of 0.56 W/cm2 for 3 minutes, while temperature changes were measured. Tumors were assessed for necrosis with hematoxylin-eosin staining. Organs were analyzed with inductively coupled plasma mass spectrometry to assess biodistribution. Therapeutic efficacy and tumor necrosis area were compared by using a one-way analysis of variance with post hoc analysis for statistically significant differences. Results The coupling efficiency was 22 µg/mg (55%). Significant differences were found between preinfusion and 24-hour postinfusion measurements of both T2 (repeated measures analysis of variance, P = .025) and T2* (P < .001). Significant differences also existed for T2* measurements between the anti-MG1 HNP and HNP-only groups (P = .034). Mean temperature ± standard deviation with PTA in the anti-MG1-coated HNP, HNP, and control groups was 50.2°C ± 7.8, 51°C ± 4.4, and 39.5°C ± 2.0, respectively. Inductively coupled plasma mass spectrometry revealed significant tumor targeting and splenic sequestration. Mean percentages of tumor necrosis in the anti-MG1-coated HNP, HNP, and control groups were 38% ± 29, 14% ± 17, and 7% ± 8, respectively (P = .043). Conclusion Targeted monoclonal antibody-conjugated HNPs can serve as a catalyst for photothermal ablation of colorectal liver metastases by increasing ablation zones. © RSNA, 2017.
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Neoplasias Colorretais/terapia , Ouro/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Terapia com Luz de Baixa Intensidade/métodos , Nanopartículas de Magnetita/uso terapêutico , Nanoconjugados/uso terapêutico , Animais , Anticorpos Monoclonais/farmacocinética , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Hipertermia Induzida/métodos , Neoplasias Hepáticas/imunologia , Mucina-5B/imunologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Crescentic IgA nephropathy (IgAN), defined as >50% crescentic glomeruli on kidney biopsy, is one of the most common causes of rapidly progressive GN. However, few studies have characterized this condition. To identify risk factors and develop a prediction model, we assessed data from patients ≥ 14 years old with crescentic IgAN who were followed ≥ 12 months. The discovery cohort comprised 52 patients from one kidney center, and the validation cohort comprised 61 patients from multiple centers. At biopsy, the mean serum creatinine (SCr) level ± SD was 4.3 ± 3.4 mg/dl, and the mean percentage of crescents was 66.4%± 15.8%. The kidney survival rates at years 1, 3, and 5 after biopsy were 57.4%± 4.7%, 45.8%± 5.1%, and 30.4%± 6.6%, respectively. Multivariate Cox regression revealed initial SCr as the only independent risk factor for ESRD (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.10 to 1.57; P=0.002). Notably, the percentage of crescents did not associate independently with ESRD. Logistic regression showed that the risk of ESRD at 1 year after biopsy increased rapidly at SCr>2.7 mg/dl and reached 90% at SCr>6.8 mg/dl (specificity=98.5%, sensitivity=64.6% for combined cohorts). In both cohorts, patients with SCr>6.8 mg/dl were less likely to recover from dialysis. Analyses in additional cohorts revealed a similar association between initial SCr and ESRD in patients with antiglomerular basement membrane disease but not ANCA-associated systemic vasculitis. In conclusion, crescentic IgAN has a poor prognosis, and initial SCr concentration may predict kidney failure in patients with this disease.
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Povo Asiático/estatística & dados numéricos , Glomerulonefrite por IGA/mortalidade , Glomerulonefrite por IGA/patologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Adulto , Idoso , Biópsia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Vasculite/mortalidade , Vasculite/patologia , Adulto JovemRESUMO
Fibrillary glomerulonephritis (FGN) is a rare kidney disease typically affecting individuals in middle age, frequently presenting with advanced renal failure, proteinuria, and hypertension. FGN can be associated with autoimmune diseases, hepatitis C infection, and malignancies. Its exact pathogenesis remains elusive, and the exact role of DnaJ homolog subfamily B member 9 is yet to be determined. On renal biopsy, FGN exhibits distinctive Congo-red-negative, nonbranching fibrils, approximately 20 nm in diameter. DnaJ homolog subfamily B member 9 immunohistochemical staining has become a gold standard for diagnosis. Atypical variants exist, including congophilic, monotypic, and crescentic FGN, highlighting the disease's heterogeneity. Treatment with immunosuppression, including rituximab, has shown variable success, with no standard therapy established. FGN often leads to end-stage kidney disease, with a median progression time of 2-4 years postdiagnosis. Kidney transplantation is a viable option for FGN-related end-stage kidney disease, but recurrence in transplanted kidneys is not rare.
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Glomerulonefrite , Humanos , Glomerulonefrite/terapia , Glomerulonefrite/diagnóstico , Glomerulonefrite/patologia , Transplante de Rim , Falência Renal Crônica/terapia , Imunossupressores/uso terapêutico , BiópsiaRESUMO
Mendelian randomization (MR) is an instrumental variable approach used to infer causal relationships between exposures and outcomes, which is becoming increasingly popular because of its ability to handle summary statistics from genome-wide association studies. However, existing MR approaches often suffer the bias from weak instrumental variables, horizontal pleiotropy and sample overlap. We introduce MRBEE (MR using bias-corrected estimating equation), a multivariable MR method capable of simultaneously removing weak instrument and sample overlap bias and identifying horizontal pleiotropy. Our extensive simulations and real data analyses reveal that MRBEE provides nearly unbiased estimates of causal effects, well-controlled type I error rates and higher power than comparably robust methods and is computationally efficient. Our real data analyses result in consistent causal effect estimates and offer valuable guidance for conducting multivariable MR studies, elucidating the roles of pleiotropy, and identifying total 42 horizontal pleiotropic loci missed previously that are associated with myopia, schizophrenia, and coronary artery disease.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Análise da Randomização Mendeliana/métodos , Humanos , Viés , Pleiotropia Genética , Doença da Artéria Coronariana/genética , Simulação por Computador , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Context. To determine the clinical-pathological features associated with cholesterol embolic renal disease, and review of literature. Design. This retrospective case series includes patients with cholesterol embolic renal disease (10 of 3087 kidney biopsies) who were diagnosed at Northwell Health, New York, between July 2017 and October 2022. Results. Cholesterol embolic renal disease is a rare disease with a prevalence of 0.32%. Four of 10 patients had intravascular interventional radiology procedures within 6 months prior to kidney biopsy. Four patients had remote interventional radiology history (6 months to 4 years). Seven patients presented with acute kidney injury; 3 patients underwent renal biopsy due to proteinuria. The average baseline creatinine was 2.0 ± 0.9â mg/dL; the creatinine at kidney biopsy and at follow-up was 4.3 ± 3.0â mg/dL and 2.8 ± 1.3â mg/dL, respectively. Eight patients had elevated serum eosinophil counts. Three patients died (mortality rate 30%) in an average follow-up of 4 months (range: 1-10 months). One patient progressed to end-stage kidney disease. The presence of cholesterol clefts is a hallmark of atherosclerotic emboli. Cholesterol clefts were present on the specimen for light microscopy (H&E and special stains) in 9 biopsies; 7 patients had cholesterol clefts in vascular lumens and/or walls. Cholesterol clefts were present on semi-thin sections for electron microscopy examination in 4 biopsies. One patient had cholesterol clefts present in semi-thin sections only. Conclusions. The clinical manifestation of cholesterol embolic renal disease in patients without recent intravascular interventional radiology history can be indolent but is associated with high mortality. Careful examination of all levels with light microscopy, including the perirenal tissue, and semi-thin sections can increase the detection rate of cholesterol embolic renal disease.
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There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci (6 independent signals) interacted with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrate that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated heritability is significant (P < 0.02) for low-density lipoprotein cholesterol and triglycerides in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.
Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Herança Multifatorial/genética , Masculino , Triglicerídeos/sangue , Feminino , Consumo de Bebidas Alcoólicas/genética , Polimorfismo de Nucleotídeo Único , Fenótipo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Fumar Cigarros/genética , Locos de Características Quantitativas , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. METHODS: Seventy-nine patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy. According to different adjuvant therapies, patients were divided into postoperative chemotherapy group (47 cases) and postoperative radiotherapy/concurrent chemoradiotherapy group (32 cases). Regimens for NAC and postoperative chemotherapy were BIP (bleomycin+ ifosfamide+ cisplatin/carboplatin) or TP (paclitaxel+ cisplatin/carboplatin). An average of 1.1±0.3 cycles of NAC and 3.4±1.2 cycles of postoperative chemotherapy were prescribed. RESULTS: Toxicities due to chemotherapy were generally tolerable. Overall response rate of NAC was 88.6%. With a median follow-up period of 42 months, the three-year progression-free survival rates of the two groups were 88.5% and 84.3%, the total survival rates were 90.3% and 86.4%, respectively. There was no statistically significant difference. The recurrent rates were 10.6% and 21.8% in the two groups. In the absence of radiotherapy, pelvic recurrence was observed in two patients; the other three had distant metastases. CONCLUSION: The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. The patients can tolerate the side effects of chemotherapy with better efficacy.
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Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias do Colo do Útero/terapia , Adenocarcinoma/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/uso terapêutico , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Histerectomia , Ifosfamida/uso terapêutico , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Paclitaxel , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/uso terapêutico , Neoplasias do Colo do Útero/patologiaRESUMO
Mendelian randomization (MR) is an instrumental variable approach used to infer causal relationships between exposures and outcomes and can apply to summary data from genome-wide association studies (GWAS). Since GWAS summary statistics are subject to estimation errors, most existing MR approaches suffer from measurement error bias, whose scale and direction are influenced by weak instrumental variables and GWAS sample overlap, respectively. We introduce MRBEE (MR using Bias-corrected Estimating Equation), a novel multivariable MR method capable of simultaneously removing measurement error bias and identifying horizontal pleiotropy. In simulations, we showed that MRBEE is capable of effectively removing measurement error bias in the presence of weak instrumental variables and sample overlap. In two independent real data analyses, we discovered that the causal effect of BMI on coronary artery disease risk is entirely mediated by blood pressure, and that existing MR methods may underestimate the causal effect of cannabis use disorder on schizophrenia risk compared to MRBEE. MRBEE possesses significant potential for advancing genetic research by providing a valuable tool to study causality between multiple risk factors and disease outcomes, particularly as a large number of GWAS summary statistics become publicly available.
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Mendelian Randomization (MR) has been widely applied to infer causality of exposures on outcomes in the genome wide association (GWAS) era. Existing approaches are often subject to biases from multiple sources including weak instruments, sample overlap, and measurement error. We introduce MRBEE, a computationally efficient multivariable MR method that can correct for all known biases simultaneously, which is demonstrated in theory, simulations, and real data analysis. In comparison, all existing MR methods are biased. In two independent real data analyses, we observed that the causal effect of BMI on coronary artery disease risk is completely mediated by blood pressure, and that existing MR methods drastically underestimate the causal effect of cannabis use disorder on schizophrenia risk compared to MRBEE. We demonstrate that MRBEE can be a useful tool in studying causality between multiple risk factors and a disease outcome, especially as more GWAS summary statistics are being made publicly available.
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Atypical anti-glomerular basement membrane (anti-GBM) disease is characterized by linear immunoglobulin G (IgG) deposition along the GBM without circulating IgG anti-GBM antibodies. Compared to classic anti-GBM disease, atypical anti-GBM disease tends to be milder with a more indolent course in certain cases. Moreover, pathologic disease pattern is much more heterogenous in atypical anti-GBM disease than in the classic type, which is uniformly characterized by diffuse crescentic and necrotizing glomerulonephritis. Although there is no single well-established target antigen in atypical anti-GBM disease, the target antigen (within the GBM) and the autoantibody type are hypothesized to be different from the classic type. Some patients have the same antigen as the Goodpasture antigen that are detected only by a highly sensitive technique (biosensor analysis). Some cases of atypical anti-GBM disease have autoantibodies of a different subclass restriction like IgG4, or of monoclonal nature. Antibodies targeting antigen/epitope structure other than the Goodpasture antigen can be detected using modified assays in some cases. Patients with IgA- and IgM-mediated anti-GBM disease are known to have negative circulating antibodies because conventional assays do not detect these classes of antibodies. A significant proportion of cases with atypical anti-GBM disease do not have any identifiable antibodies despite extensive evaluation. Nevertheless, extensive evaluation of atypical autoantibodies using modified assays and sensitive techniques should be attempted, if feasible. This review summarizes the recent literature on atypical anti-GBM disease.
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BACKGROUND: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow. METHODS: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy. RESULTS: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate (r=0.64; P<0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis (r=-0.85; P<0.001). CONCLUSIONS: Renal blood flow can be reliably measured from cardiac 13N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits.
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Amônia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Estudos de Viabilidade , Reprodutibilidade dos Testes , Tomografia por Emissão de Pósitrons , Rim/diagnóstico por imagem , Perfusão , FibroseRESUMO
There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G×E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identified and confirmed 5 loci (6 independent signals) interacting with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrated that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated contribution ranges from 1.76% to 14.05% of SNP heritability of serum lipids in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.
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This review describes the clinical and pathological features of oxalate nephropathy (ON), defined as a syndrome of decreased renal function associated with deposition of calcium oxalate crystals in kidney tubules. We review the different causes of hyperoxaluria, including primary hyperoxaluria, enteric hyperoxaluria and ingestion-related hyperoxaluria. Recent case series of biopsy-proven ON are reviewed in detail, as well as the implications of these series. The possibility of antibiotic use predisposing to ON is discussed. Therapies for hyperoxaluria and ON are reviewed with an emphasis on newer treatments available and in development. Promising research avenues to explore in this area are discussed.