Characterization of septin expression in normal and fibrotic kidneys

Chronic kidney disease (CKD) is characterized by the loss of nephrons and worsening organ-fibrosis that leads to deterioration and ultimately the total breakdown of kidney function. Renal fibrosis has become a major public health problem worldwide and necessitates hemodialysis and kidney transplantation in affected patients. CKD is mainly characterized by the activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix components, causing the disruption of the normal tissue architecture of the kidney. Septins are GTPase proteins associated with membranes, actin filaments, and microtubules and are undoubtedly crucial for cytoskeleton organization. Although some septins are involved in liver fibrosis, they have not been investigated in the context of renal fibrosis. Here, we show that numerous septins are expressed in the healthy kidney and demonstrate in fibrotic mouse kidneys that various septins are remarkably up-regulated in the tubulointerstitium compared to contralateral control kidneys. We observed the same findings in human fibrotic kidneys. In both healthy and fibrotic kidneys, septins are coexpressed with extracellular matrix components, reinforcing the structural function of septins as cytoskeletal components. Furthermore, we could show in septin 8-deficient mice that septin 8 is dispensable for the formation of renal fibrosis, and that no other septin was compensatory changed in kidneys compared to wild-type mice

Management and endovascular therapy of ureteroarterial fistulas: experience from a single center and review of the literature

Background!#!Ureteroarterial fistula (UAF) is a rare but potentially life threatening disease. The aim of this study was to evaluate the outcome of endovascular therapy for UAF treatment.!##!Methods!#!This retrospective case series evaluates a single center experience of percutaneous stent graft (SG) angioplasty and/or coil embolization for UAF. Patient follow-up included technical and early clinical success, complications and revisional procedures. We also conducted a systematic review of the literature reporting on endovascular UAF management.!##!Results!#!We identified 17 UAF in 16 patients (12 male, 4 female, mean age 69.8 ± 11.3 years) who underwent endovascular UAF therapy at our tertiary hospital. All patients presented with hematuria. 5/17 (29.4%) presented with flank pain, in 7 (41.2%) cases patients were in hypovolemic shock. Risk factors of UAF included chronic indwelling ureteral stents in all fistulas, major pelvic surgery in 13 cases (76.5%). In 6 cases (35.3%) SG were placed from the common iliac artery (CIA) to the external iliac artery (EIA) following coil embolization of the proximal internal iliac artery (IIA). SG placement without previous coil embolization was performed in 10 fistulas (58.8%). In one case only coil embolization of the IIA was performed. Mean follow-up was 654 (range: 1-3269) days. All procedures were technically successful and no procedure related deaths occurred during follow-up. During the initial hospital stay hematuria disappeared in 14/17 cases (82.4%). Overall, four patients suffered recurrent hematuria, which in three cases resolved after a secondary intervention. One recurrent UAF related death occurred during follow-up 229 days after initial treatment. A total of 152 UAF cases were additionally analyzed from our systematic literature review: SG placement with or without embolization was performed in 140 cases (92.1%) while embolization alone was done in 12 cases (7.9%). Complications included UAF recurrence (18/152, 11.8%), SG thrombosis (7/140, 5%), and SG infections (5/140, 3.6%) with an overall complications rate of 13.8%. Five patients died due to UAF (3.3%).!##!Conclusion!#!Endovascular therapy offers high technical success rates and rapid bleeding control of UAF. Severe complications like SG occlusions or SG infections are rare but significant. Antibiotic treatment and single anti-platelet therapy improve SG durability as well as close and long follow-up to timely perform repeated endovascular or surgical treatment if necessary.!##!Evidence-based medicine!#!Level 4, case series

Apparently normal kidney development in mice with conditional disruption of ANG II-AT1 receptor genes in FoxD1-positive stroma cell precursors

An intact renin-angiotensin system involving ANG II type 1 (AT(1)) receptors is crucial for normal kidney development. It is still unclear in which cell types AT(1) receptor signaling is required for normal kidney development, maturation, and function. Because all kidney cells deriving from stroma progenitor cells express AT 1 receptors and because stromal cells fundamentally influence nephrogenesis and tubular maturation, we investigated the relevance of AT(1) receptors in stromal progenitors and their descendants for renal development and function. For this aim, we generated and analyzed mice with conditional deletion of AT(1A )receptor in the FoxD1 cell lineage in combination with global disruption of the AT(1B) receptor gene. These FoxD1-AT1ko mice developed normally. Their kidneys showed neither structural nor functional abnormalities compared with wild-type mice, whereas in isolated perfused FoxDl-AT1ko kidneys, the vasoconstrictor and renin inhibitory effects of ANG II were absent. In vivo, however, plasma renin concentration and renal renin expression were normal in FoxD1-AT1ko mice, as were blood pressure and glomerular filtration rate. These findings suggest that a strong reduction of AT(1) receptors in renal stromal progenitors and their descendants does not disturb normal kidney development

Angiotensin II Short-Loop Feedback

The activity of the renin a Ootensin aldosterone system is triggered by the release of the protease renin from the kidneys, which in turn is controlled in the sense of negative feedback loops, It is widely assumed that Ang II (angiotensin II) directly inhibits renin expression and secretion via a short-loop feedback by an effect on renin-producing cells (RPCs) mediated by AT(1) (Aug II type 1) receptors. Because the concept of such a direct short-loop negative feedback control, which originates mostly from in vitro experiments, has not yet been systematically proven in vivo, we aimed to test the validity of this concept by studying the regulation of renin synthesis and secretion in mice lacking Aug II-AT(1) receptors on RPCs. We found that RPCs of the kidney express Ang II-AT(1) receptors. Mice with conditional deletion of Ang II-AT, receptors in RPCs were normal with regard to the number of renin cells, renal renin mRNA, and plasma renin concentrations. Renin expression and secretion of these mice responded to Ang I (angiotensin I) converting enzyme inhibition and to Ang II infusion like in wild-type (WT) controls. In summary, we did not obtain evidence that Ang II-AT(1) receptors on RPCs arc of major relevance for the normal regulation of renin expression and secretion in mice. Therefore, we doubt the existence of a direct negative feedback function of Ang II on RPCs

Efficient Claustrum Segmentation in T2-weighted Neonatal Brain MRI Using Transfer Learning from Adult Scans

Purpose Intrauterine claustrum and subplate neuron development have been suggested to overlap. As premature birth typically impairs subplate neuron development, neonatal claustrum might indicate a specific prematurity impact; however, claustrum identification usually relies on expert knowledge due to its intricate structure. We established automated claustrum segmentation in newborns. Methods We applied a deep learning-based algorithm for segmenting the claustrum in 558 T2-weighted neonatal brain MRI of the developing Human Connectome Project (dHCP) with transfer learning from claustrum segmentation in T1-weighted scans of adults. The model was trained and evaluated on 30 manual bilateral claustrum annotations in neonates. Results With only 20 annotated scans, the model yielded median volumetric similarity, robust Hausdorff distance and Dice score of 95.9%, 1.12 mm and 80.0%, respectively, representing an excellent agreement between the automatic and manual segmentations. In comparison with interrater reliability, the model achieved significantly superior volumetric similarity (p = 0.047) and Dice score (p < 0.005) indicating stable high-quality performance. Furthermore, the effectiveness of the transfer learning technique was demonstrated in comparison with nontransfer learning. The model can achieve satisfactory segmentation with only 12 annotated scans. Finally, the model’s applicability was verified on 528 scans and revealed reliable segmentations in 97.4%. Conclusion The developed fast and accurate automated segmentation has great potential in large-scale study cohorts and to facilitate MRI-based connectome research of the neonatal claustrum. The easy to use models and codes are made publicly available