From kidney injury to kidney cancer.

Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer).

Analytical evaluation of direct bicarbonate measurement with the new gem premier chemstat in hemodialysis patients.

GEM Premier ChemSTAT is a whole-blood analyzer designed for providing a rapid basic metabolic panel, inclusive of creatinine and blood urea nitrogen, with the unique characteristic of providing measured bicarbonate (HCO3-) levels. The aim of this work was to evaluate the clinical performance of HCO3- assessment with this analyser in a real-life hemodialysis setting. Imprecision was calculated at different HCO3- levels, along with assay comparison with Gem Premier 4000 analysers. GEM Premier ChemSTAT displayed an imprecision and a bias (in comparison to GEM Premier 4000) for HCO3- of 0.4% and 37.3% at 20.8 mmol/L, 1.2% and 25.6% at 16.4 mmol/L, and 2.1% and 11.6% at 11.5 mmol/L, respectively, using three levels of HCO3- quality control sample ChemSTAT System Evaluator. At direct comparison with the GEM Premier 4000 in the hemodialysis setting, Bland-Altman analysis of HCO3- levels evidenced a bias (µ) of -4.9 (95% CI, -5.2 to -4.7) mmol/L. Such difference was attenuated by recalculating the GEM ChemSTAT expected HCO3- values from pH and pCO2 using the Henderson Hasselbach equation, µ=-0.07 (95%CI, -0.19 to 0.05) mmol/L (p = .24). In conclusion, our results show a remarkable difference between the HCO3- values reported by GEM ChemSTAT or GEM 4000. New reference values for GEM ChemSTAT HCO3- shall hence be defined according to our findings. We suggest that further investigation and a re-evaluation of the reference range should be made before extending the clinical use of this device.

A systematic review to identify whether perfusate biomarkers produced during hypothermic machine perfusion can predict graft outcomes in kidney transplantation.

There is good evidence to support the use of hypothermic machine perfusion (HMP) over static cold storage as the favoured preservation method for deceased donor kidneys. However, the utility of HMP as a tool to assess the viability of kidneys for transplant is unclear. There is a need to determine whether perfusate biomarkers produced during HMP can predict post-transplant outcomes and assess the suitability of organs for transplantation. Three different databases (MEDLINE, Embase, Transplant Library) were screened to 31 May 2019. Articles were included if a relationship was reported between one or more perfusate biomarkers and post-transplant outcomes. Studies were assessed and graded for methodological quality and strength of evidence. Glutathione S-transferase was the most promising biomarker for predicting delayed graft function, but its predictive ability was at best moderate. Analysis of primary nonfunction rates was challenging due to low occurrence rates and small sample sizes. Existing studies are limited in quality and have not yielded biomarkers for kidneys undergoing HMP that are able to predict post-transplant outcomes with sufficient accuracy to support routine clinical use. Further studies with larger samples and more robust methodology are needed. (PROSPERO registration: CRD42019121161).

Distillation of an End-to-End Oracle for Face Verification and Recognition Sensors.

Face recognition functions are today exploited through biometric sensors in many applications, from extended security systems to inclusion devices; deep neural network methods are reaching in this field stunning performances. The main limitation of the deep learning approach is an inconvenient relation between the accuracy of the results and the needed computing power. When a personal device is employed, in particular, many algorithms require a cloud computing approach to achieve the expected performances; other algorithms adopt models that are simple by design. A third viable option consists of model (oracle) distillation. This is the most intriguing among the compression techniques since it permits to devise of the minimal structure that will enforce the same I/O relation as the original model. In this paper, a distillation technique is applied to a complex model, enabling the introduction of fast state-of-the-art recognition capabilities on a low-end hardware face recognition sensor module. Two distilled models are presented in this contribution: the former can be directly used in place of the original oracle, while the latter incarnates better the end-to-end approach, removing the need for a separate alignment procedure. The presented biometric systems are examined on the two problems of face verification and face recognition in an open set by using well-agreed training/testing methodologies and datasets.

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review.

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from January 1, 2015 to May 31, 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.

Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View.

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

Dose Prescription and Delivery in Neonates With Congenital Heart Diseases Treated With Continuous Veno-Venous Hemofiltration.

OBJECTIVES: Renal replacement therapy may be required for acute kidney injury treatment in neonates with complex cardiac conditions. Continuous veno-venous hemofiltration is applied safely in this population but no published recommendations for dose prescription in neonates currently exist. The aim of our study was to evaluate the effects of a relatively small dialysis dose on critically ill neonates. DESIGN: Retrospective analysis of clinical charts. SETTING: Pediatric Cardiac ICU. PATIENTS: Ten critically ill neonates with severe acute kidney injury were analyzed. The primary indication for continuous veno-venous hemofiltration initiation was severe fluid overload with oligoanuria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median (range) age and weight were 3 days (1-12 d) and 2.6 kg (2.1-4.2 kg), respectively, whereas the median continuous veno-venous hemofiltration duration was 17 days (3-63 d). Median prescribed blood flow rate, replacement fluid rate, and net ultrafiltration rate were 12 mL/min (9-50 mL/min), 100 mL/hr (40-200 mL/hr), and 20 mL/hr (5-45 mL/hr), respectively. The median effluent-based continuous veno-venous hemofiltration dose was 35 mL/kg/hr (11-66 mL/kg/hr), whereas the median delivered daily Kt/V per session (24 hr) was 0.5 (0.01-1.8). However, for treatment sessions lasting less than or equal to 12 versus greater than or equal to 12 hours per session, the median prescribed effluent dose was 41 (11-66) and 32 (17-60) mL/kg/hr, respectively (p = 0.06), whereas the delivered creatinine daily Kt/V values were 0.3 (0.01-0.9) and 0.9 (0.5-1.8), respectively (p < 0.0001). An inverse correlation was found between delivered daily Kt/V and the blood concentration differences of both creatinine (r = -0.3; p = 0.0093) and urea (r = -0.3; p = 0.0028) measured at the end and the beginning of a 24-hour treatment. The decrease of creatinine concentration was significantly greater during 24-hour treatment sessions with a delivered daily Kt/V greater than 0.9 than during those with daily Kt/V less than 0.9. CONCLUSIONS: Based on these findings, we propose on a provisional basis the use of daily Kt/V as a measure of continuous renal replacement therapy adequacy for critically ill neonates.

Dialytic dose in pediatric continuous renal replacement therapy patients.

Although universally recognized as a crucial component of renal replacement therapy (RRT), dialytic dose has not been investigated in children with renal failure, differently from the adult population. Consequently, clear indications on the adequacy of continuous RRT in pediatric population is currently missing and wide variations in clinical practice exist worldwide. Fluid balance has been identified as a key factor in affecting outcomes these patients. Nonetheless, the concept and the precise evaluation of the dialytic dose for continuous pediatric RRT seems crucial, especially in light of the small body surface area of neonates and infants that might result into a difficult dose calculation. The present review clearly demonstrates that dialytic dose in pediatric RRT has been underestimated by scientific literature. Nowadays, the absence of any specific dedicated prospective study and the tendency to overlook theoretical basis of pediatric dialytic dose have led to the absence of a standard prescription: worldwide clinical practice ranges from very high doses to lower ones, also depending on different ways of estimating patients' sizes and solutes' volume of distribution. Large structured studies are warranted in order to define a reference dialytic dose for critically ill children, capable to cope an adequate solute control to gentle and safe treatments.

Prostate cancer detection and complications of MRI-targeted prostate biopsy using cognitive registration, software-assisted image fusion or in-bore guidance: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Three primary strategies for MRI-targeted biopsies (TB) are available: Cognitive TB (COG-TB), MRI-US Fusion TB (FUS-TB), and In Bore TB (IB-TB). Despite nearly a decade of practice, a consensus on the preferred approach is lacking, with previous studies showing comparable PCa detection rates among the three methods. METHODS: We conducted a search of PubMed, EMBASE, PubMed, Web of Science, and Scopus databases from 2014 to 2023, to identify studies comparing at least two of the three methods and reporting clinically significant PCa (csPCa) detection rates. The primary and secondary outcomes were to compare the csPCa and insignificant prostate cancer (iPCa, ISUP GG 1) detection rates between TB techniques. The tertiary outcome was to compare the complication rate between TB techniques. Detection rates were pooled using random-effect models. Planned sensitivity analyses included subgroup analysis according to the definition of csPCa and positive MRI, previous biopsy status, biopsy route, prostate volume, and lesion characteristics. RESULTS: A total of twenty studies, involving 4928 patients, were included in the quantitative synthesis. The meta-analysis unveiled comparable csPCa detection rates among COG-TB (0.37), FUS-TB (0.39), and IB-TB (0.47). iPCa detection rate was also similar between TB techniques (COG-TB: 0.12, FUS-TB: 0.17, IB-TB: 0.18). All preplanned sensitivity analyses were conducted and did not show any statistically significant difference in the detection of csPCa between TB methods. Complication rates, however, were infrequently reported, and when available, no statistically significant differences were observed among the techniques. CONCLUSIONS: This unique study, exclusively focusing on comparative research, indicates no significant differences in csPCa and iPCa detection rates between COG-TB, FUS-TB, and IB-TB. Decisions between these techniques may extend beyond diagnostic accuracy, considering factors such as resource availability and operator preferences. Well-designed prospective studies are warranted to refine our understanding of the optimal approach for TB in diverse clinical scenarios.

Vascular access for hemodialysis in Italy: What a national survey reveals.

BACKGROUND: Since in Italy there are no official data on vascular access (VA) for hemodialysis the Vascular Access Project Group (VAPG) of the Italian Society of Nephrology (SIN) designed a national survey. METHODS: A 35-question survey was designed and sent it to the Italian facilities through the SIN website. The basic questions were the prevalence, the location, and the surveillance of VA, the bedside use of ultrasound, the use of fluoroscopy for central venous catheter (CVC) placement, and of buttonhole technique, the role of nephrologist in the access creation. RESULT: The questionnaire was completed in June 2022 by 161 facilities. The survey registered 15,499 patients, approximately one-third of the Italian dialysis population. The prevalence of arteriovenous fistula (AVF), arteriovenous Graft (AVG), and CVC were 61.8%, 3.7%, and 34.5% respectively. The AVF location was 50% in distal forearm, 20% in meanproximal forearm, 30% in upper arm. For AVF creation, nephrologists were involved in 72% of facilities while for CVC placement in 62%. As regards VA monitoring, 21% of the facilities did not have a surveillance protocol; 60% did not register AVF thrombosis and 53% did not register CVC infections. Most of facilities use the fluoroscope during CVC placement, 37% when needed, and 22% never. Ultrasound-guided puncture of complex AVFs was used by 80% of facilities. Buttonhole puncture was used in 5% of patients. CONCLUSIONS: Some considerations emerge from the survey data: (1) The increasing CVC prevalence compared to DOPPS 5 study. (2) The low rate of AVG prevalence. (3) The nephrologist is the operator in many VA procedures. (4) The fluoroscopy for CVC placement and the US-guide puncture of the complex AVF are widely used in most facilities. (5) The practice of the buttonhole is not widespread. (6) When the operator is the nephrologist more distal fistulas are performed.

Factors associated with successful liberation from continuous renal replacement therapy in children and young adults: analysis of the worldwide exploration of renal replacement outcomes collaborative in Kidney Disease Registry.

PURPOSE: Continuous renal replacement therapy (CRRT) is used for supportive management of acute kidney injury (AKI) and disorders of fluid balance (FB). Little is known about the predictors of successful liberation in children and young adults. We aimed to identify the factors associated with successful CRRT liberation. METHODS: The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease study is an international multicenter retrospective study (32 centers, 7 nations) conducted from 2015 to 2021 in children and young adults (aged 0-25 years) treated with CRRT for AKI or FB disorders. Patients with previous dialysis dependence, tandem extracorporeal membrane oxygenation use, died within the first 72 h of CRRT initiation, and those who never had liberation attempted were excluded. Patients were categorized based on first liberation attempt: reinstituted (resumption of any dialysis within 72 h) vs. success (no receipt of dialysis for ≥ 72 h). Multivariable logistic regression was used to identify factors associated with successful CRRT liberation. RESULTS: A total of 622 patients were included: 287 (46%) had CRRT reinstituted and 335 (54%) were successfully liberated. After adjusting for sepsis at admission and illness severity parameters, several factors were associated with successful liberation, including higher VIS (vasoactive-inotropic score) at CRRT initiation (odds ratio [OR] 1.35 [1.12-1.63]), higher PELOD-2 (pediatric logistic organ dysfunction-2) score at CRRT initiation (OR 1.71 [1.24-2.35]), higher urine output prior to CRRT initiation (OR 1.15 [1.001-1.32]), and shorter CRRT duration (OR 0.19 [0.12-0.28]). CONCLUSIONS: Inability to liberate from CRRT was common in this multinational retrospective study. Modifiable and non-modifiable factors were associated with successful liberation. These results may inform the design of future clinical trials to optimize likelihood of CRRT liberation success.

Major Adverse Kidney Events in Pediatric Continuous Kidney Replacement Therapy.

Importance: Continuous kidney replacement therapy (CKRT) is increasingly used in youths with critical illness, but little is known about longer-term outcomes, such as persistent kidney dysfunction, continued need for dialysis, or death. Objective: To characterize the incidence and risk factors, including liberation patterns, associated with major adverse kidney events 90 days after CKRT initiation (MAKE-90) in children, adolescents, and young adults. Design, Setting, and Participants: This international, multicenter cohort study was conducted among patients aged 0 to 25 years from The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry treated with CKRT for acute kidney injury or fluid overload from 2015 to 2021. Exclusion criteria were dialysis dependence, concurrent extracorporeal membrane oxygenation use, or receipt of CKRT for a different indication. Data were analyzed from May 2 to December 14, 2023. Exposure: Patient clinical characteristics and CKRT parameters were assessed. CKRT liberation was classified as successful, reinstituted, or not attempted. Successful liberation was defined as the first attempt at CKRT liberation resulting in 72 hours or more without return to dialysis within 28 days of CKRT initiation. Main Outcomes and Measures: MAKE-90, including death or persistent kidney dysfunction (dialysis dependence or ≥25% decline in estimated glomerular filtration rate from baseline), were assessed. Results: Among 969 patients treated with CKRT (529 males [54.6%]; median [IQR] age, 8.8 [1.7-15.0] years), 630 patients (65.0%) developed MAKE-90. On multivariable analysis, cardiac comorbidity (adjusted odds ratio [aOR], 1.60; 95% CI, 1.08-2.37), longer duration of intensive care unit admission before CKRT initiation (aOR for 6 days vs 1 day, 1.07; 95% CI, 1.02-1.13), and liberation pattern were associated with MAKE-90. In this analysis, patients who successfully liberated from CKRT within 28 days had lower odds of MAKE-90 compared with patients in whom liberation was attempted and failed (aOR, 0.32; 95% CI, 0.22-0.48) and patients without a liberation attempt (aOR, 0.02; 95% CI, 0.01-0.04). Conclusions and Relevance: In this study, MAKE-90 occurred in almost two-thirds of the population and patient-level risk factors associated with MAKE-90 included cardiac comorbidity, time to CKRT initiation, and liberation patterns. These findings highlight the high incidence of adverse outcomes in this population and suggest that future prospective studies are needed to better understand liberation patterns and practices.

Automatic Differentiation for Inverse Problems in X-ray Imaging and Microscopy.

Computational techniques allow breaking the limits of traditional imaging methods, such as time restrictions, resolution, and optics flaws. While simple computational methods can be enough for highly controlled microscope setups or just for previews, an increased level of complexity is instead required for advanced setups, acquisition modalities or where uncertainty is high; the need for complex computational methods clashes with rapid design and execution. In all these cases, Automatic Differentiation, one of the subtopics of Artificial Intelligence, may offer a functional solution, but only if a GPU implementation is available. In this paper, we show how a framework built to solve just one optimisation problem can be employed for many different X-ray imaging inverse problems.

Advances in sparse dynamic scanning in spectromicroscopy through compressive sensing.

Scanning microscopies and spectroscopies like X-ray Fluorescence (XRF), Scanning Transmission X-ray Microscopy (STXM), and Ptychography are of very high scientific importance as they can be employed in several research fields. Methodology and technology advances aim at analysing larger samples at better resolutions, improved sensitivities and higher acquisition speeds. The frontiers of those advances are in detectors, radiation sources, motors, but also in acquisition and analysis software together with general methodology improvements. We have recently introduced and fully implemented an intelligent scanning methodology based on compressive sensing, on a soft X-ray microscopy beamline. This demonstrated sparse low energy XRF scanning of dynamically chosen regions of interest in combination with STXM, yielding spectroimaging data in the megapixel-range and in shorter timeframes than were previously not feasible. This research has been further developed and has been applied to scientific applications in biology. The developments are mostly in the dynamic triggering decisional mechanism in order to incorporate modern Machine Learning (ML) but also in the suitable integration of the method in the control system, making it available for other beamlines and imaging techniques. On the applications front, the method was previously successfully used on different samples, from lung and ovarian human tissues to plant root sections. This manuscript introduces the latest methodology advances and demonstrates their applications in life and environmental sciences. Lastly, it highlights the auxiliary development of a mobile application, designed to assist the user in the selection of specific regions of interest in an easy way.

External Validation of the IMPROD-MRI Volumetric Model to Predict the Utility of Systematic Biopsies at the Time of Targeted Biopsy.

Background: The aim of this study was to validate externally a nomogram that relies on MRI volumetric parameters and clinical data to determine the need for a standard biopsy in addition to a target biopsy for men with suspicious prostate MRI findings. Methods: We conducted a retrospective analysis of a prospectively maintained database of 469 biopsy-naïve men who underwent prostate biopsies. These biopsies were guided by pre-biopsy multiparametric Magnetic Resonance Imaging (mpMRI) and were performed at two different institutions. We included men with a PIRADSsv 2.1 score from 3 to 5. Each patient underwent both an MRI-ultrasound fusion biopsy of identified MRI-suspicious lesions and a systematic biopsy according to our protocol. The lesion volume percentage was determined as the proportion of cancer volume on MRI relative to the entire prostate volume. The study's outcomes were iPCa (Gleason Grade Group 1) and csPCa (Gleason Grade Group > 1). We evaluated the model's performance using AUC decision curve analyses and a systematic analysis of model-derived probability cut-offs in terms of the potential to avoid diagnosing iPCa and to accurately diagnose csPCa. Results: The nomogram includes age, PSA value, prostate volume, PIRADSsv 2.1 score, percentage of MRI-suspicious lesion volume, and lesion location. AUC was determined to be 0.73. By using various nomogram cut-off thresholds (ranging from 5% to 30%), it was observed that 19% to 58% of men could potentially avoid undergoing standard biopsies. In this scenario, the model might miss 0% to 10% of diagnosis of csPCa and could prevent identifying 6% to 31% of iPCa cases. These results are in line with findings from the multi-institutional external validation study based on the IMPROD trial (n = 122) and the MULTI-IMPROD trial (n = 262). According to DCA, the use of this nomogram led to an increased overall net clinical benefit when the threshold probability exceeded 10%. Conclusions: This study supports the potential value of a model relying on MRI volumetric measurements for selecting individuals with clinical suspicion of prostate cancer who would benefit from undergoing a standard biopsy in addition to a targeted biopsy.

A modular software framework for the design and implementation of ptychography algorithms.

Computational methods are driving high impact microscopy techniques such as ptychography. However, the design and implementation of new algorithms is often a laborious process, as many parts of the code are written in close-to-the-hardware programming constructs to speed up the reconstruction. In this article, we present SciComPty, a new ptychography software framework aiming at simulating ptychography datasets and testing state-of-the-art and new reconstruction algorithms. Despite its simplicity, the software leverages GPU accelerated processing through the PyTorch CUDA interface. This is essential for designing new methods that can readily be employed. As an example, we present an improved position refinement method based on Adam and a new version of the rPIE algorithm, adapted for partial coherence setups. Results are shown on both synthetic and real datasets. The software is released as open-source.

Microfluidics for 3D Cell and Tissue Cultures: Microfabricative and Ethical Aspects Updates.

The necessity to improve in vitro cell screening assays is becoming ever more important. Pharmaceutical companies, research laboratories and hospitals require technologies that help to speed up conventional screening and therapeutic procedures to produce more data in a short time in a realistic and reliable manner. The design of new solutions for test biomaterials and active molecules is one of the urgent problems of preclinical screening and the limited correlation between in vitro and in vivo data remains one of the major issues. The establishment of the most suitable in vitro model provides reduction in times, costs and, last but not least, in the number of animal experiments as recommended by the 3Rs (replace, reduce, refine) ethical guiding principles for testing involving animals. Although two-dimensional (2D) traditional cell screening assays are generally cheap and practical to manage, they have strong limitations, as cells, within the transition from the three-dimensional (3D) in vivo to the 2D in vitro growth conditions, do not properly mimic the real morphologies and physiology of their native tissues. In the study of human pathologies, especially, animal experiments provide data closer to what happens in the target organ or apparatus, but they imply slow and costly procedures and they generally do not fully accomplish the 3Rs recommendations, i.e., the amount of laboratory animals and the stress that they undergo must be minimized. Microfluidic devices seem to offer different advantages in relation to the mentioned issues. This review aims to describe the critical issues connected with the conventional cells culture and screening procedures, showing what happens in the in vivo physiological micro and nano environment also from a physical point of view. During the discussion, some microfluidic tools and their components are described to explain how these devices can circumvent the actual limitations described in the introduction.

Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice.

Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.

Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors.

Continuous Renal Replacement Therapy in Critically Ill Children in the Pediatric Intensive Care Unit: A Retrospective Analysis of Real-Life Prescriptions, Complications, and Outcomes.

Introduction: Severe acute kidney injury is a common finding in the Pediatric Intensive Care Unit (PICU), however, Continuous Renal Replacement Therapy (CRRT) is rarely applied in this setting. This study aims to describe our experience in the rate of application of CRRT, patients' clinical characteristics at admission and CRRT initiation, CRRT prescription, predictors of circuit clotting, short- and long-term outcomes. Methods: A 6-year single center retrospective study in a tertiary PICU. Results: Twenty-eight critically ill patients aged 0 to 18 years received CRRT between January 2012 and December 2017 (1.4% of all patients admitted to PICU). Complete clinical and CRRT technical information were available for 23/28 patients for a total of 101 CRRT sessions. CRRT was started, on average, 40 h (20-160) after PICU admission, mostly because of fluid overload. Continuous veno-venous hemodiafiltration and systemic heparinization were applied in 83.2 and 71.3% of sessions, respectively. Fifty-nine sessions (58.4%) were complicated by circuit clotting. At multivariate Cox-regression analysis, vascular access caliber larger than 8 Fr [HR 0.37 (0.19-0.72), p = 0.004] and regional citrate anticoagulation strategy [HR 0.14 (0.03-0.60), p = 0.008] were independent protective factors for clotting. PICU mortality rate was 42.8%, and six survivors developed chronic kidney disease (CKD), within an average follow up of 3.5 years. Conclusions: CRRT is uncommonly applied in our PICU, mostly within 2 days after admission and because of fluid overload. Larger vascular access and citrate anticoagulation are independent protective factors for circuit clotting. Patients' PICU mortality rate is high and survival often complicated by CKD development.