The Rogosin Institute

The proximal tubule of the nephron resorbs water, amino acids and glucose, and its energy demands are high. Formation of the cellular machinery for energy production is an essential step in proximal tubule epithelial cell (PTC) differentiation, and this report focuses on how mitochondria in nascent PTCs are redistributed from their initial apical position to their ultimate basolateral location. We found that mitochondria move from the apical to basolateral side of the PTC coincident with the initiation of lumen flow and that proximal tubules deficient in filtration (aglomerular mice and kidney organoids) maintain their mitochondria in the apical position, indicating that flow is necessary and sufficient for localization. Further, we show that mitochondrial localization depends on the activity of LRRK2 in vitro and in vivo . Modeling the effect of fluid flow on PTCs demonstrates that LRRK2 activity is regulated by fluid shear stress, providing an explanation for how onset of flow in the newly differentiated proximal tubule may trigger the apical-to-basolateral dissemination of mitochondria that forms the template for subsequent PTC maturation. Our findings indicate that mitochondrial redistribution is one component of a cellular program in the nascent PTC that drives function and that this process is regulated by flow.

The formation of functional epithelial tubules is critical for the development and maintenance of many organ systems. While the mechanisms of tubule formation by epithelial cells are well studied, the process of tubule anastomosis-where tubules connect to form a continuous network-remains poorly understood. In this study, we utilized single-cell RNA sequencing to analyze embryonic mouse kidney tubules undergoing anastomosis. Our analysis identified hepatocyte growth factor (HGF) as a key potential mediator of this process. To investigate this further, we developed an assay using epithelial spheroids with fluorescently tagged apical surfaces, allowing us to visualize and quantify tubule-tubule connections. Our results demonstrate that HGF promotes tubule anastomosis, and it does so through the MAPK signaling pathway and MMPs, independently of cell proliferation. Remarkably, treatment with HGF and collagenase was sufficient to induce tubule anastomosis in embryonic mouse kidneys. These findings provide a foundational understanding of how to enhance the formation of functional tubular networks. This has significant clinical implications for the use of in vitro-grown kidney tissues in transplant medicine, potentially improving the success and integration of transplanted tissues.

ABSTRACTWith the increasing frequency and severity of disasters and the increasing number of patients living with kidney disease, on dialysis and with transplants around the world, the need for kidney care in humanitarian settings is increasing. Almost all humanitarian emergencies pose a threat to kidney health because all treatments are highly susceptible to interruption, and interruption can be deadly. Providing support for people requiring dialysis in humanitarian settings can be complex and is associated with many trade-offs. The global kidney care community must become familiar with the ethics, principles and duties essential to meeting the overarching goals of ethical and effective disaster relief. Ethics principles and values must be considered on the individual, public health and global levels. The wellbeing of a single patient must be considered in the context of the competing needs of many others, and optimal treatment may not be possible due to resource constraints. Public health ethics principles, including considerations of triage and resource allocation, maximization of benefit and feasibility, often become directly relevant at the bedside. Individuals delivering humanitarian relief must be well trained, competent, respectful and professional, while involved organizations need to uphold the highest professional and ethical standards. There may be dissonance between ethical guidance and practical realities in humanitarian settings, which for inexperienced individuals may present significant challenges. Sustaining dialysis care in emergencies brings these issues starkly to the fore. Preparedness for dialysis in emergencies is an ethical imperative that mandates multisectoral stakeholder engagement and action, development of surge response plans, clinical and ethics guidance, and transparent priority setting. This manuscript outlines common ethics challenges and considerations that apply in all humanitarian actions, and illustrates their relevance to kidney care as a whole, using examples of how these may apply to dialysis and kidney disaster relief efforts in humanitarian settings.

Patients with autosomal dominant polycystic kidney disease (ADPKD) develop cysts in the kidneys, liver, spleen, pancreas, prostate, and arachnoid spaces. In addition, spinal meningeal diverticula have been reported. To determine whether spinal meningeal diverticula are associated with ADPKD, we compared their prevalence in subjects with ADPKD with a control cohort without ADPKD. Subjects with ADPKD and age- and sex-matched controls without ADPKD undergoing abdominal MRI from the midthorax to the pelvis from 2003 to 2023 were retrospectively evaluated for spinal meningeal diverticula by 4 blinded observers. The prevalence of spinal meningeal diverticula in ADPKD was compared with that in control subjects, using t tests and correlated with clinical and laboratory data and MR imaging features, including cyst volumes and cyst counts. Identification of spinal meningeal diverticula in ADPKD (n = 285, median age, 47; interquartile range [IQR], 37-56 years; 54% female) and control (n = 285, median age, 47; IQR, 37-57 years; 54% female) subjects had high interobserver agreement (pairwise Cohen κ = 0.74). Spinal meningeal diverticula were observed in 145 of 285 (51%) subjects with ADPKD compared with 66 of 285 (23%) control subjects without ADPKD (P < .001). Spinal meningeal diverticula in ADPKD were more prevalent in women (98 of 153 [64%]) than men (47 of 132 [36%], P < .001). The mean number of spinal meningeal diverticula per affected subject with ADPKD was 3.6 ± 2.9 compared with 2.4 ± 1.9 in controls with cysts (P < .001). The median volume (IQR, 25%-75%) of spinal meningeal diverticula was 400 (IQR, 210-740) mm3 in those with ADPKD compared with 250 (IQR, 180-440) mm3 in controls (P < .001). The mean spinal meningeal diverticulum diameter was greater in the sacrum (7.3 [SD, 4.1] mm) compared with thoracic (5.4 [SD, 1.8] mm) and lumbar spine (5.8 [SD, 2.0] mm), (P < .001), suggesting that hydrostatic pressure contributed to enlargement. ADPKD has a high prevalence of spinal meningeal diverticula, particularly in women.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) can lead to polycystic liver disease (PLD), characterized by liver cysts. Although majority of the patients are asymptomatic, massively enlarged liver secondary to PLD can cause discomfort, and compression on adjacent structures requiring cyst aspiration/fenestration, partial liver resection, or liver transplantation. Monitoring PLD by measuring liver volume fails to track the early stages when liver cyst volume is too small to affect liver volume.PurposeTo improve PLD assessment in the early stages by automating detection and segmentation of liver cysts using deep learning (DL) models.Materials and MethodsA self-configured UNet-based platform (nnU-Net) was trained with 40 ADPKD subjects with liver cysts annotated by a radiologist. Internal (n = 7), External (n = 10), and test-retest reproducibility (n = 17) validations included macro- and micro-level performance metrics: patient-level Dice scores (PDice), along with voxel-level true positive rates (VTPR), as well as analysis of time saved in a model-assisted scenario. Additionally, we assessed human-level reliability in liver cyst segmentation and evaluated the model’s test-retest reproducibility. We further compared liver volume vs cyst volume for tracking disease in a subject with 16+ years follow-up.ResultsThe model achieved an 82% ± 11% PDice and a 75% ± 15% VTPR on the internal test sets (n = 7 patients), and 80% ± 12% Dice score and a 91% ± 7% VTPR on the external test sets (n = 10 patients). It excelled particularly in detecting small liver cysts, a challenging task for manual annotation. This efficiency translated to a median of 91% (IQR: 14%) reduction in annotation time compared to manual labeling. Test-retest assessment demonstrated excellent reproducibility, with coefficients of variation of 94% for liver cyst fraction and 92% for cyst count.ConclusionDL automation of liver cyst segmentations demonstrates potential to improve tracking of liver cyst volume in polycystic liver disease.

Background and purpose The objective is to demonstrate feasibility of quantitative susceptibility mapping (QSM) in autosomal dominant polycystic kidney disease (ADPKD) patients and to compare imaging findings with traditional T1/T2w magnetic resonance imaging (MRI). Methods Thirty-three consecutive patients (11 male, 22 female) diagnosed with ADPKD were initially selected. QSM images were reconstructed from the multiecho gradient echo data and compared to co-registered T2w, T1w and CT images. Complex cysts were identified and classified into distinct subclasses based on their imaging features. Prevalence of each subclass was estimated. Results QSM visualized two renal calcifications measuring 9 and 10 mm, and three pelvic phleboliths measuring 2 mm but missed 24 calcifications measuring 1mm or less and 1 larger calcification at the edge of the field of view. A total of 121 complex T1 hyperintense/T2 hypointense renal cysts were detected. 52 (43%) cysts appeared hyperintense on QSM consistent with hemorrhage; 60 (49%) cysts were isointense with respect to simple cysts and normal kidney parenchyma, while the remaining 9 (7%) were hypointense. The presentation of the latter two complex cyst subtypes is likely indicative of proteinaceous composition without hemorrhage. Conclusions Our results indicate that QSM of ADPKD kidneys is possible and uniquely suited to detect large renal calculi without ionizing radiation, and able to identify properties of complex cysts unattainable with traditional approaches.

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