Peter Boor

Autopsies are the foundation of evidence-based medicine and gold standard for determining causes of death. A potential causal relationship between COVID-19 vaccination and death remains a subject of debate, however multidisciplinary, multicentric national autopsy studies are missing. N = 486 eligible SARS-CoV-2 vaccinated autopsy cases from 14 German pathology, neuropathology and legal medicine university centres between 2021 and 2024 were available via the German National Autopsy Registry. For comparison COVID-19 autopsies were included ( n = 385 cases, all performed before the vaccination campaign in Germany started). A previously established causality algorithm was applied in a consensus assessment of potential causality between vaccine administration and an adverse event following immunization (AEFI). N = 176 cases with a post vaccination interval ≤ 28d were included into analyses. In a single case of allergic reaction, in 5/8 cases of either myocarditis ( n = 4 cases) or perimyocarditis ( n = 1 case), and 9/26 cases of thromboembolism, the consensus process resulted in a potential AEFI in these cases, but no definite causality. In n = 3 cases in which the cause of death remained unclear after autopsy, no potential AEFI could be established. In SARS-CoV-2 positive autopsy cases without vaccination, thromboembolism was documented as cause of death in 18/385 cases and myocarditis in 2/385 cases. In conclusion, autopsies are a valuable tool to assess adverse effects. Currently, post vaccination autopsy numbers are too low to draw conclusions on the general population or to identify rare AEFI signals. As part of pandemic preparedness, international guidelines for post vaccination autopsy procedures, diagnostics and interpretation are necessary. Autopsy registries can support this collective effort.

The shortage of donor organs has led to an increased use of extended-criteria donors and donation after circulatory death for kidney transplantation, both of which are associated with graft injury. Although machine perfusion (MP) offers a preservation strategy, the most beneficial approach for kidneys with respect to effective graft preservation remains unclear. We compared oxygenated hypothermic (HMP) and normothermic machine perfusion (NMP) using a murine kidney perfusion model regarding intra-graft immune cell composition, viability, and inflammatory responses. NMP resulted in more severe tubular injury, accompanied by increased immune cell mobilization out of the graft. NMP increased early apoptosis among kidney-resident immune-cell populations, whereas endothelial cells showed increased late apoptosis after both strategies. Proximal tubular-cell apoptosis remained comparable to naïve tissue, and neither modality reduced reactive oxygen species levels. Both protocols induced antioxidant and hypoxia-responsive genes compared with static cold storage, while NMP elicited a stronger inflammatory response. Treatment with the senolytic ABT-263 demonstrated the model’s feasibility for investigating renal injury, cellular viability, and immune activation during MP.

Background: Activated parietal epithelial cells (PECs) and podocytes are key effector cells in the development of crescentic glomerulonephritis and focal segmental glomerulosclerosis (FSGS). Platelet-derived growth factor (PDGF)-C has been found to be important for tubulointerstitial fibrosis development, but its relevance for crescentic glomerulonephritis and FSGS was previously unknown. Methods: To address this, expression analyses for both PDGF-C and its receptor PDGFRα were carried out in mouse and human kidney tissues. To further elucidate a functional role of PDGF-C, the murine nephrotoxic nephritis model of crescentic glomerulonephritis was induced in a) Pdgfc -deficient mice, b) mice treated with a neutralizing PDGF-C antibody, and c) Pax8-cre::Pdgfc ^fl / ^fl mice with conditional Pdgfc deletion in kidney epithelial cells. We also subjected the collapsing FSGS model of the anti-Thy1.1 transgenic mouse to pharmacological PDGF-C inhibition. The studies were supplemented by PEC in vitro analyses. Results: Our data showed that PDGF-C was upregulated in PECs and expressed de novo in podocytes under disease conditions. It promoted the proliferation and activation of primary as well as conditionally immortalized PECs in vitro . In both the genetic and pharmacological PDGF-C intervention studies in murine crescentic glomerulonephritis and FSGS, significant improvements in glomerular crescent formation, glomerular sclerosis, renal inflammation and kidney function parameters were observed upon PDGF-C deficiency or antagonism. Mechanistically, transcription factor FOXM1 was identified as a mediator of disease-related PDGF-C expression in PECs. Conclusions: Our studies identified epithelial PDGF-C as a contributor to disease progression in crescentic glomerulonephritis and FSGS, acting in part through the activation of parietal epithelial cells.

Introductory paragraph: End-stage kidney disease (ESKD) is a major driver of cardiovascular disease (CVD) and requires dialysis treatment leading to a unique metabolic phenotype with cyclic transitions between accumulation and clearance of uremic toxins ^1–3 . Although ESKD patients display the highest cardiovascular mortality among CKD patients, the effect of cyclic uremia on cardiovascular disease remains subject to discussion ^4–6 . Existing mouse models rely on induction of kidney injury and do not resolve the interconnected pathophysiological effects of metabolic, hypertensive and endocrine renal failure ^7–9 . They are therefore unable to distinguish uremia-driven effects from well-established drivers of cardiovascular disease such as hypertension. Here, we established a simple, reproducible, and sex-inclusive mouse model of uremia in absence of kidney injury or hypertension leveraging a bistable vesico-peritoneal shunt (VPS). Strikingly, we identify cyclic uremia as an independent driver of ESKD-induced CVD, that induces heart failure with preserved ejection fraction (HFpEF), vascular inflammation and immunosenescence. As such, the VPS represents the first preclinical model that enables investigation of cyclic uremia as a driver of cardiovascular disease.

Aims: Patients with chronic kidney disease (CKD) display a reduced survival following myocardial infarction (MI). As the underlying mechanisms remain unclear, we examined the impact of CKD on cardiac remodeling and function post-MI using a mouse model of adenine-induced CKD. Methods and results: After MI, CKD mice showed a stronger cardiac dysfunction compared to non-CKD controls. While immunohistochemical and immunofluorescence analyses did not reveal changes in cardiomyocyte apoptosis, infarction size, or myofibroblast content, CKD mice exhibited an increased number of circulating myeloid cells post-infarction and more neutrophil infiltration in the heart. Combining RNAseq, untargeted kinome profiling, western blotting, and mass spectrometry revealed that post-MI, CKD enhanced cardiac oxidative stress and the acute stress complex S100A8/A9 in circulation and the heart, and enforced cardiac MAP-kinase p38 activation and NR4A1 phosphorylation as pathways underlying cardiomyocyte dysfunction. S100A8/A9 also exerted an acute detrimental impact on calcium flux and sarcomere shortening in cardiomyocytes ex vivo. Increased myeloid cell-derived S100A8/A9 expression was confirmed in the infarcted human heart by single-nucleus RNAseq, and CKD patients had higher post-infarction S100A8/A9 levels compared to patients without kidney dysfunction. Furthermore, integrating metabolomics, RNAseq, and mitochondrial analysis uncovered a disturbed cardiac metabolism with impaired glycolysis, a reduced glycerol-3-phosphate-shuttle, and a reduced Coenzyme A-bioavailability in CKD vs. non-CKD mice post-MI. These alterations were associated with poorer cardiac performance post-MI, without intrinsic defects in mitochondrial function observed. Conclusion: Our study reveals innate immune activation, inflammation, oxidative stress, and metabolic alterations indicative of reduced glycolytic entry and CoA bioavailability along with aggravated cardiac dysfunction post-MI in CKD compared to non-CKD conditions, independent of infarct size, and with poorer cardiac performance in CKD associated with the cardiac metabolic alterations. Combined, this could contribute to the worsened outcome of CKD patients post-MI and reveals cardiac metabolism in CKD as an interesting translational research target.

Understanding pathological processes is crucial for the diagnosis, prediction and prognostication of kidney diseases. Although progress has been made in non-invasive diagnostic approaches, many pathological processes and diseases mainly manifest in the kidney tissue, necessitating comprehensive analyses of kidney samples. Cellular and molecular analyses of the kidney, including single-cell omics approaches, have identified novel disease mechanisms. However, these non-spatial methods lack information on cellular localization and tissue organization, which is crucial for understanding cell-cell interactions. Such information is particularly important for the kidney, which has many different cell types and intricate architecture. Developments in spatial omics technologies address this challenge by enabling the simultaneous analysis of molecular profiles and spatial context. Advances in three-dimensional imaging technologies, including non-destructive approaches, may provide additional layers of structural information. Integration of spatial omics technologies, such as transcriptomics, epigenomics and metabolomics, with imaging and computational pathology approaches, such as pathomics, has the potential to further advance understanding of the pathophysiology of kidney diseases. In the future, such approaches could become part of the diagnostic workflow in pathology. In the meantime, they hold great promise to aid the identification of diagnostic, prognostic and predictive biomarkers as well as novel therapeutic targets, and thereby facilitate drug discovery.

Background: Artificial intelligence (AI) can improve stroke imaging workflows, but its computational carbon footprint remains poorly quantified. We estimated carbon dioxide equivalent (CO ₂ eq) emissions from AI use in US stroke management and evaluated carbon‐aware mitigation. Methods: We combined TriNetX neuroimaging utilization data with Global Burden of Disease stroke burden estimates for 2018 to 2019. Imaging utilization rates were aligned by state, year, stroke type, sex, and age group. We modeled 2 AI scenarios: Minimal AI, defined as one 2‐dimensional classification model and one 2‐dimensional segmentation model; and Ideal AI, defined as two 2‐dimensional classification models, two 3‐dimensional segmentation models, and one 3‐dimensional classification model. Model energy use was converted to CO ₂ eq using state‐level grid carbon intensity from Electricity Maps. Results: Ideal AI generated 16 375.09 metric tons CO ₂ eq/year (95% CI, 16 340.83–16 409.36), compared with 7692.70 metric tons CO ₂ eq/year (95% CI, 7676.08–7709.32) for Minimal AI. Computed tomography angiography and magnetic resonance imaging were the largest modality contributors. Per‐capita emissions varied substantially by state, reflecting local grid composition. Relocating AI‐related processing to cleaner‐energy states reduced modeled Ideal AI emissions to 7408.68 metric tons CO ₂ eq/year (95% CI, 7386.99–7430.38), a 54.75% reduction. Conclusions: AI‐assisted stroke imaging has a measurable carbon footprint that depends on model intensity, imaging modality, and grid carbon intensity. Carbon‐aware routing of computation offers an immediate mitigation strategy while preserving clinical AI use.

Tissue inflammation is shaped by reciprocal interactions between immune cells and stromal niches, yet how leukemic myelopoiesis rewires these circuits remains poorly understood. Here, we identify suppression of interferon regulatory factor 8 (IRF8) in hematopoietic cells as a driver of inflammatory bone marrow niche remodeling in chronic-phase myeloid leukemia (CP-CML). IRF8 expression was reduced in human and murine CML and restored following interferon-α therapy. In mice, hematopoietic IRF8 deficiency induced aberrant neutrophil expansion, extramedullary hematopoiesis, stromal activation and early marrow fibrosis. Single-cell transcriptomics revealed that IRF8-deficient neutrophils engaged perivascular stromal cells, CXCL12-abundant reticular cells and endothelial cells through S100A8/A9–TLR4 and TGF-β–integrin signaling, associated with hypoxia, vascular remodeling and extracellular matrix programs. Mechanistically, IRF8 directly bound the S100a8 locus and restrained the alarmin program in myeloid cells. Conversely, an IRF8-deficient niche amplified BCR–ABL1-driven leukemia and inflammatory alarmin production. These findings identify IRF8 as a hematopoietic regulator of inflammatory neutrophil–stromal communication and reveal how its suppression promotes pathological remodeling of the leukemic bone marrow niche.

IgA nephropathy (IgAN) is a major cause of late graft loss after kidney transplantation, yet evidence for newly approved IgAN-specific therapies in this setting is scarce. We report a young male transplant recipient with biopsy-proven recurrent IgAN seven years after living-donor transplantation. Treatment with targeted-release budesonide (nefecon) was associated with a delayed and incomplete antiproteinuric response, clinically relevant systemic glucocorticoid-related adverse effects and progressive graft function decline. After discontinuation of nefecon, combined therapy with sparsentan and empagliflozin resulted in sustained albuminuria reduction, stabilization of graft function, improved blood pressure control, and resolution of metabolic complications. This case highlights challenges and opportunities in integrating novel IgAN therapies into post-transplant care.