The podocytes' inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling.

Podocytes form the kidney filtration barrier and continuously adjust to external stimuli to preserve their integrity even in the presence of inflammation. It was suggested that canonical toll-like receptor signaling, mediated by the adaptor protein MYD88, plays a crucial role in initiating inflammatory responses in glomerulonephritis (GN). We explored the influence of podocyte-intrinsic MYD88 by challenging wild-type (WT) and podocyte-specific Myd88 knockout (MyD88pko) mice, with a model of experimental GN (nephrotoxic nephritis, NTN). Next-generation sequencing revealed a robust upregulation of inflammatory pathways and changes in cytoskeletal and cell adhesion proteins in sorted podocytes from WT mice during disease. Unchallenged MyD88pko mice were healthy and showed no proteinuria, normal kidney function and lacked morphological changes. During NTN, MyD88pko exhibited a transient increase in proteinuria in comparison to littermates, while histological damage, podocyte ultrastructure in STED imaging and frequencies of infiltrating immune cells by flow cytometry were unchanged. MYD88-deficiency led to subtle changes in the podocyte transcriptome, without a significant impact on the overall podocyte response to inflammation, presumably through MYD88-independent signaling pathways. In conclusion, our study reveals a comprehensive analysis of podocyte adaptation to an inflammatory environment on the transcriptome level, while MYD88-deficiency had only limited impact on the course of GN suggesting additional signaling through MYD88-independent signaling.

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial.

Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Dual-layer dual-energy CT-derived pulmonary perfusion for the differentiation of acute pulmonary embolism and chronic thromboembolic pulmonary hypertension.

OBJECTIVES: To evaluate dual-layer dual-energy computed tomography (dlDECT)-derived pulmonary perfusion maps for differentiation between acute pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This retrospective study included 131 patients (57 patients with acute PE, 52 CTEPH, 22 controls), who underwent CT pulmonary angiography on a dlDECT. Normal and malperfused areas of lung parenchyma were semiautomatically contoured using iodine density overlay (IDO) maps. First-order histogram features of normal and malperfused lung tissue were extracted. Iodine density (ID) was normalized to the mean pulmonary artery (MPA) and the left atrium (LA). Furthermore, morphological imaging features for both acute and chronic PE, as well as the combination of histogram and morphological imaging features, were evaluated. RESULTS: In acute PE, normal perfused lung areas showed a higher mean and peak iodine uptake normalized to the MPA than in CTEPH (both p < 0.001). After normalizing mean ID in perfusion defects to the LA, patients with acute PE had a reduced average perfusion (IDmean,LA) compared to both CTEPH patients and controls (p < 0.001 for both). IDmean,LA allowed for a differentiation between acute PE and CTEPH with moderate accuracy (AUC: 0.72, sensitivity 74%, specificity 64%), resulting in a PPV and NPV for CTEPH of 64% and 70%. Combining IDmean,LA in the malperfused areas with the diameter of the MPA (MPAdia) significantly increased its ability to differentiate between acute PE and CTEPH (sole MPAdia: AUC: 0.76, 95%-CI: 0.68-0.85 vs. MPAdia + 256.3 * IDmean,LA - 40.0: AUC: 0.82, 95%-CI: 0.74-0.90, p = 0.04). CONCLUSION: dlDECT enables quantification and characterization of pulmonary perfusion patterns in acute PE and CTEPH. Although these lack precision when used as a standalone criterion, when combined with morphological CT parameters, they hold potential to enhance differentiation between the two diseases. CLINICAL RELEVANCE STATEMENT: Differentiating between acute PE and CTEPH based on morphological CT parameters is challenging, often leading to a delay in CTEPH diagnosis. By revealing distinct pulmonary perfusion patterns in both entities, dlDECT may facilitate timely diagnosis of CTEPH, ultimately improving clinical management. KEY POINTS: • Morphological imaging parameters derived from CT pulmonary angiography to distinguish between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension lack diagnostic accuracy. • Dual-layer dual-energy CT reveals different pulmonary perfusion patterns between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension. • The identified parameters yield potential to enable more timely identification of patients with chronic thromboembolic pulmonary hypertension.

Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis.

SIGNIFICANCE STATEMENT: Treatment of acute, crescentic glomerulonephritis (GN) consists of unspecific and potentially toxic immunosuppression. T cells are central in the pathogenesis of GN, and various checkpoint molecules control their activation. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown potential for restraining inflammation in other T-cell-mediated disease models. To investigate its role in GN in a murine model of crescentic nephritis, the authors induced nephrotoxic nephritis in BTLA-deficient mice and wild-type mice. They found that BTLA has a renoprotective role through suppression of local Th1-driven inflammation and expansion of T regulatory cells and that administration of an agonistic anti-BTLA antibody attenuated experimental GN. These findings suggest that antibody-based modulation of BTLA may represent a treatment strategy in human glomerular disease. BACKGROUND: Modulating T-lymphocytes represents a promising targeted therapeutic option for glomerulonephritis (GN) because these cells mediate damage in various experimental and human GN types. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown its potential to restrain inflammation in other T-cell-mediated disease models. Its role in GN, however, has not been investigated. METHODS: We induced nephrotoxic nephritis (NTN), a mouse model of crescentic GN, in Btla -deficient ( BtlaKO ) mice and wild-type littermate controls and assessed disease severity using functional and histologic parameters at different time points after disease induction. Immunologic changes were comprehensively evaluated by flow cytometry, RNA sequencing, and in vitro assays for dendritic cell and T-cell function. Transfer experiments into Rag1KO mice confirmed the observed in vitro findings. In addition, we evaluated the potential of an agonistic anti-BTLA antibody to treat NTN in vivo . RESULTS: The BtlaKO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells. Single-cell RNA sequencing showed increased renal T-cell activation and positive regulation of the immune response. Although BTLA-deficient regulatory T cells (Tregs) exhibited preserved suppressive function in vitro and in vivo , BtlaKO T effector cells evaded Treg suppression. Administration of an agonistic anti-BTLA antibody robustly attenuated NTN by suppressing nephritogenic T effector cells and promoting Treg expansion. CONCLUSIONS: In a model of crescentic GN, BTLA signaling effectively restrained nephritogenic Th1 cells and promoted regulatory T cells. Suppression of T-cell-mediated inflammation by BTLA stimulation may prove relevant for a broad range of conditions involving acute GN.