Recurrent complement-mediated Hemolytic uremic syndrome after kidney transplantation.

Hereditary forms of hemolytic uremic syndrome (HUS), formerly known as atypical HUS, typically involve mutations in genes encoding for components of the alternative pathway of complement, therefore they are often referred to as complement-mediated HUS (cHUS). This condition has a high risk of recurrence in the transplanted kidney, leading to accelerated graft loss. The availability of anti-complement component C5 antibody eculizumab has enabled successful transplantation with a notably reduced recurrence rate and improved prognosis. Open questions are related to the potential for complement inhibitor discontinuation, ideal timing of treatment withdrawal, and patient selection based on genetic abnormalities. Our review delves into the pathophysiology, classification, genetic predispositions, and management strategies for cHUS in the native and transplant kidneys.

Micro tensile tester measurement of biomechanical properties and adhesion force of microtubule-polymerization-inhibited cancer cells.

Both mechanical and adhesion properties of cancer cells are complex and reciprocally related to migration, invasion, and metastasis with large cell deformation. Therefore, we evaluated these properties for human cervical cancer cells (HeLa) simultaneously using our previously developed micro tensile tester system. For efficient evaluation, we developed image analysis software to modify the system. The software can analyze the tensile force in real time. The modified system can evaluate the tensile stiffness of cells to which a large deformation is applied, also evaluate the adhesion strength of cancer cells that adhered to a culture substrate and were cultured for several days with their adhesion maturation. We used the modified system to simultaneously evaluate the stiffness of the cancer cells to which a large deformation was applied and their adhesion strength. The obtained results revealed that the middle phase of tensile stiffness and adhesion force of the microtubule-depolymerized group treated with colchicine (an anti-cancer drug) (stiffness, 13.4 ± 7.5 nN/%; adhesion force, 460.6 ± 258.2 nN) were over two times larger than those of the control group (stiffness, 5.0 ± 3.5 nN/%; adhesion force, 168.2 ± 98.0 nN). Additionally, the same trend was confirmed with the detailed evaluation of cell surface stiffness using an atomic force microscope. Confocal fluorescence microscope observations showed that the stress fibers (SFs) of colchicine-treated cells were aligned in the same direction, and focal adhesions (FAs) of the cells developed around both ends of the SFs and aligned parallel to the developed direction of the SFs. There was a possibility that the microtubule depolymerization by the colchicine treatment induced the development of SFs and FAs and subsequently caused an increment of cell stiffness and adhesion force. From the above results, we concluded the modified system would be applicable to cancer detection and anti-cancer drug efficacy tests.

Recurrent C3 glomerulopathy after kidney transplantation.

The complement system is part of innate immunity and is pivotal in protecting the body against pathogens and maintaining host homeostasis. Activation of the complement system is triggered through multiple pathways, including antibody deposition, a mannan-binding lectin, or activated complement deposition. C3 glomerulopathy (C3G) is a rare glomerular disease driven by complement dysregulation with high post-transplantation recurrence rates. Its treatment is mainly based on immunosuppressive therapies, specifically mycophenolate mofetil and glucocorticoids. Recent years have seen significant progress in understanding complement biology and its role in C3G pathophysiology. New complement-tergeting treatments have been developed and initial trials have shown promising results. However, challenges persist in C3G, with recurrent post-transplantation cases leading to suboptimal outcomes. This review discusses the pathophysiology and management of C3G, with a focus on its recurrence after kidney transplantation.

Effects of sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, and their combination on albuminuria in diabetic patients.

AIMS: Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta-analysis to investigate the effects of SGLT2-Is, MRAs and their combination on albuminuria in type 2 DM. METHODS: We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2-Is, MRAs + SGLT2-Is, or a placebo in patients with type 2 DM with a urinary albumin-creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. RESULTS: This meta-analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2-Is and MRAs was associated with lower albuminuria compared with the use of SGLT2-Is, MRAs, or the placebo alone [mean difference (95% CI): -34.19 (-27.30; -41.08), -32.25 (-24.53; -39.97) and -65.22 (-57.97; -72.47), respectively]. Treatment with SGLT2-Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): -31.03 (-28.35; -33.72) and -32.97 (-29.68; -36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2-Is. Sensitivity analyses showed similar results. CONCLUSION: Combination therapy with SGLT2-Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2-Is or MRAs alone.

Effects of glucagon-like peptide-1 receptor agonists on patients with heart failure: a meta-analysis of randomized controlled trials.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events (MACE) and heart failure in patients with type 2 diabetes mellitus (T2DM). However, these outcomes are not similarly demonstrated in those with prior heart failure in subgroup analyses of several randomized controlled trials (RCTs). We evaluated the effect of GLP-1RAs on MACE and heart failure admissions for T2DM patients with a previous history of heart failure. METHODS: We searched PubMed and EMBASE through March 2022 to identify RCTs examining the effects of GLP-1RAs compared with placebo on MACE and heart failure admission in T2DM patients with a history of heart failure. MACE were mainly defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. We performed a meta-analysis with a random-effects model. RESULTS: Our analysis included subgroup analyses of 7 RCTs enrolling a total of 8,965 patients with T2DM and heart failure. Pooled analysis demonstrated a significantly decreased MACE (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99; P = 0.039; I2 = 18.1%) in the GLP-1RAs group. In contrast, the rate of heart failure admission was not significantly different between the two groups (hazard ratio, 1.03; 95% confidence interval, 0.91-1.16; P = 0.67; I2 = 0.0%). CONCLUSION: GLP-1RAs significantly reduced MACE in T2DM patients with prior heart failure compared with the placebo group but did not affect the risk of heart failure admission.

MPO-ANCA-associated vasculitis after the Pfizer/BioNTech SARS-CoV-2 vaccination.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has demonstrated high efficacy at preventing coronavirus disease 2019 (COVID-19) and a favorable safety profile, however it has also been reported that COVID-19 vaccines may put increase of immune-mediated disease. We herein report a case of MPO-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis following the mRNA vaccine BNT162b2 (Pfizer/BioNTech) for COVID-19. Although the causal relationship between vaccine and ANCA-associated vasculitis is uncertain, environmental and genetic factors may have set the stage for the development of vasculitis, and the vaccine may have triggered a domino effect.

Macroscopic and microscopic analysis of the mechanical properties and adhesion force of cells using a single cell tensile test and atomic force microscopy: Remarkable differences in cell types.

Many experimental techniques have been reported to provide knowledge of the mechanical behavior of cells from biomechanical viewpoints, however, it is unclear how the intercellular structural differences influence macroscopic and microscopic mechanical properties of cells. The aim of our study is to clarify the comprehensive mechanical properties and cell-substrate adhesion strength of cells, and the correlation with intracellular structure in different cell types. We developed an originally designed micro tensile tester, and performed a single cell tensile test to estimate whole cell tensile stiffness and adhesion strength of normal vascular smooth muscle cells (VSMCs) and cervical cancer HeLa cells: one half side of the specimen cell was lifted up by a glass microneedle, then stretched until the cell detached from the substrate, while force was simultaneously measured. The tensile stiffness and adhesion strength were 49 ± 10 nN/% and 870 ± 430 nN, respectively, in VSMCs (mean ± SD, n = 8), and 19 ± 17 nN/% and 320 ± 160 nN, respectively, in HeLa cells (n = 9). The difference was more definite in the surface elastic modulus map obtained by atomic force microscopy, indicating that the internal tension of the actin cytoskeleton was significantly higher in VSMCs than in HeLa cells. Structural analysis with confocal microscopy revealed that VSMCs had a significant alignment of F-actin cytoskeleton with mature focal adhesion, contrary to the randomly oriented F-actin with smaller focal adhesion of HeLa cells, indicating that structural arrangement of the actin cytoskeleton and their mechanical tension generated the differences in cell mechanical properties and adhesion forces. The finding strongly suggests that the mechanical and structural differences in each cell type are deeply involved with their physiological functions.