simmrd: An open-source tool to perform simulations in Mendelian randomization.

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.

Membranous-like glomerulopathy with masked monotypic IgG deposits: A single center case series.

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.

MRBEE: A bias-corrected multivariable Mendelian randomization method.

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.

Updates on the Diagnosis and Management of Fibrillary Glomerulonephritis.

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.

Cholesterol Embolic Renal Disease: Experience of a Large Healthcare System.

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 ± 0.9 mg/dL; the creatinine at kidney biopsy and at follow-up was 4.3 ± 3.0 mg/dL and 2.8 ± 1.3 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.

An approach to identify gene-environment interactions and reveal new biological insight in complex traits.

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.