Measuring practice preference variation for quality improvement in neonatal respiratory care.

OBJECTIVES: The authors sought to measure and compare practice preference variation in neonatal respiratory care within and between neonatal intensive care units (NICUs) using the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT). STUDY DESIGN: Eleven NICUs completed the NSIGHT between 2019 and 2021. Net preference was measured by mean response; agreement was ranked by standard distribution of response values. Heat maps showed comparisons between NICUs and disciplines. RESULTS: NICUs and individuals agreed most often on use of pressure support with mandatory ventilation and on use of non-invasive positive pressure ventilation for apnea. High preference variation surrounded decisions for invasive ventilation versus continuous positive airway pressure for extremely low birth weight infants. Preference difference was most frequent between neonatologists and nurses. CONCLUSIONS: Patterns of practice preference variation in neonatal respiratory care are specific to clinical scenario. Measuring preference variation may inform psychology of change and strengthen quality improvement efforts.

Neonatal respiratory care practice among level III and IV NICUs in New England.

OBJECTIVES: To assess respiratory care guidelines and explore variations in management of very low birth weight (VLBW) infants within a collaborative care framework. Additionally, to gather clinical leaders' perspectives on guidelines and preferences for ventilation modalities. STUDY DESIGN: Leaders from each NICU participated in a practice survey regarding the prevalence of unit clinical guidelines, and management, at many stages of care. RESULTS: Units have an average of 4.3 (±2.1) guidelines, of 9 topics queried. Guideline prevalence was not associated with practice or outcomes. An FiO2 requirement of 0.3-0.4 and a CPAP of 6-7 cmH2O, are the most common thresholds for surfactant administration, which is most often done after intubation, and followed by weaning from ventilatory support. Volume targeted ventilation is commonly used. Extubation criteria vary widely. CONCLUSIONS: Results identify trends and areas of variation and suggest that the presence of guidelines alone is not predictive of outcome.

Human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis in hypoxic kidney injury.

Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). The mitochondrial-rich proximal tubular epithelial cells (PTEC) are uniquely sensitive to hypoxia and thus, are pivotal in propagating the sustained tubular loss of AKI-to-CKD transition. Here, we examined the role of PTEC-derived small extracellular vesicles (sEV) in propagating the 'wave of tubular death'. Ex vivo patient-derived PTEC were cultured under normoxia (21 % O2) and hypoxia (1 % O2) on Transwell inserts for isolation and analysis of sEV secreted from apical versus basolateral PTEC surfaces. Increased numbers of sEV were secreted from the apical surface of hypoxic PTEC compared with normoxic PTEC. No differences in basolateral sEV numbers were observed between culture conditions. Biological pathway analysis of hypoxic-apical sEV cargo identified distinct miRNAs linked with cellular injury pathways. In functional assays, hypoxic-apical sEV selectively induced ferroptotic cell death (↓glutathione peroxidase-4, ↑lipid peroxidation) in autologous PTEC compared with normoxic-apical sEV. The addition of ferroptosis inhibitors, ferrostatin-1 and baicalein, attenuated PTEC ferroptosis. RNAse A pretreatment of hypoxic-apical sEV also abrogated PTEC ferroptosis, demonstrating a role for sEV RNA in ferroptotic 'wave of death' signalling. In line with these in vitro findings, in situ immunolabelling of diagnostic kidney biopsies from AKI patients with clinical progression to CKD (AKI-to-CKD transition) showed evidence of ferroptosis propagation (increased numbers of ACSL4+ PTEC), while urine-derived sEV (usEV) from these 'AKI-to-CKD transition' patients triggered PTEC ferroptosis (↑lipid peroxidation) in functional studies. Our data establish PTEC-derived apical sEV and their intravesicular RNA as mediators of tubular lipid peroxidation and ferroptosis in hypoxic kidney injury. This concept of how tubular pathology is propagated from the initiating insult into a 'wave of death' provides novel therapeutic check-points for targeting AKI-to-CKD transition.

Measuring practice preference variation for quality improvement: development of the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT).

BACKGROUND: Understanding behavioural psychology and the human side of change are guiding principles for quality improvement (QI). Tools to measure these to guide improvement efforts are lacking. METHODS: We created a clinical vignette-based survey to measure provider preferences for respiratory care in the neonatal intensive care unit. Fourteen vignettes were included, each vignette offering two reasonable practice choices. Responses were based on a 5-point Likert scale, ranging from neutral to strong preference for either choice. The survey was completed by physicians, nurses, advanced practice providers and respiratory therapists in 2017 and again in 2019. Net preference was measured as the median value of responses, and agreement was measured as the SD of responses. Net preference and agreement were assessed for all responses, by discipline, and by year. RESULTS: Response rates were 51% of all staff in 2017 and 57% in 2019. Vignettes asking about non-invasive respiratory support showed more defined net preferences and higher agreement between years, coinciding with QI efforts and guideline implementation in this area during the interval time. Results on other areas of practice were consistent between years. Discipline comparisons showed nurses and physicians agreed the least often. Six response patterns were identified, ranging from net preference and high agreement to no net preference and low agreement. CONCLUSION: We propose this survey, called the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool, is a novel method for measurement of hospital unit psychology and culture. Demonstrated improvement where QI efforts were focused and consistency in results in other areas support the validity of this tool. Measuring the human side of change may impact QI efforts.

High risk clear cell renal cell carcinoma microenvironments contain protumour immunophenotypes lacking specific immune checkpoints.

Perioperative immune checkpoint inhibitor (ICI) trials for intermediate high-risk clear cell renal cell carcinoma (ccRCC) have failed to consistently demonstrate improved patient outcomes. These unsuccessful ICI trials suggest that the tumour infiltrating immunophenotypes, termed here as the immune cell types, states and their spatial location within the tumour microenvironment (TME), were unfavourable for ICI treatment. Defining the tumour infiltrating immune cells may assist with the identification of predictive immunophenotypes within the TME that are favourable for ICI treatment. To define the immunophenotypes within the ccRCC TME, fresh para-tumour (pTME, n = 2), low-grade (LG, n = 4, G1-G2) and high-grade (HG, n = 4, G3-G4) tissue samples from six patients with ccRCC presenting at a tertiary referral hospital underwent spatial transcriptomics sequencing (ST-seq). Within the generated ST-seq datasets, immune cell types and states, termed here as exhausted/pro-tumour state or non-exhausted/anti-tumour state, were identified using multiple publicly available single-cell RNA and T-cell receptor sequencing datasets as references. HG TMEs revealed abundant exhausted/pro-tumour immune cells with no consistent increase in expression of PD-1, PD-L1 and CTLA4 checkpoints and angiogenic genes. Additional HG TME immunophenotype characteristics included: pro-tumour tissue-resident monocytes with consistently increased expression of HAVCR2 and LAG3 checkpoints; an exhausted CD8+ T cells sub-population with stem-like progenitor gene expression; and pro-tumour tumour-associated macrophages and monocytes within the recurrent TME with the expression of TREM2. Whilst limited by a modest sample size, this study represents the largest ST-seq dataset on human ccRCC. Our study reveals that high-risk ccRCC TMEs are infiltrated by exhausted/pro-tumour immunophenotypes lacking specific checkpoint gene expression confirming that HG ccRCC TME are immunogenic but not ICI favourable.

Hospitalizations Among Adults With CKD in Public Renal Specialty Practices: A Retrospective Study From Queensland, Australia.

Rationale & Objective: Little is known about hospital admissions in nondialysis patients with chronic kidney disease (CKD) before death or starting kidney replacement therapy (KRT). Study Design: Retrospective observational cohort study. Setting & Participants: Hospitalizations among 7,201 patients with CKD from 10 public renal clinics in Queensland (QLD), enrolled in the CKD.QLD registry starting in May 2011, were followed for 25,496.34 person-years until they started receiving KRT or died, or until June 30, 2018. Predictors: Demographic and clinical characteristics of patients with CKD. Outcomes: Hospital admissions. Analytical Approach: We evaluated the association of demographic and clinical features with hospitalizations, length of hospital stay, and cost. Results: Approximately 81.5% of the patients were admitted at least once, with 42,283 admissions, costing Australian dollars (AUD) 231 million. The average number of admissions per person-year was 1.7, and the cost was AUD 9,060, 10 times and 2 times their Australian averages, respectively. Single (1-day) admissions constituted 59.2% of all the hospital episodes, led by neoplasms (largely chemotherapy), anemia, CKD-related conditions and eye conditions (largely cataract extractions), but only 14.8% of the total costs. Approximately 41% of admissions were >1-day admissions, constituting 85.2% of the total costs, with cardiovascular conditions, respiratory conditions, CKD-related conditions, and injuries, fractures, or poisoning being the dominant causes. Readmission within 30 days of discharge constituted >42% of the admissions and 46.8% costs. Admissions not directly related to CKD constituted 90% of the admissions and costs. More than 40% of the admissions and costs were through the emergency department. Approximately 19% of the hospitalized patients and 27% of the admissions did not have kidney disease mentioned as either principal or associate causes. Limitations: Variable follow-up times because of different dates of consent. Conclusions: The hospital burden of patients with CKD is mainly driven by complex multiday admissions and readmissions involving comorbid conditions, which may not be directly related to their CKD. Strategies to prevent these complex admissions and readmissions should minimize hospital costs and outcomes. Plain-Language Summary: We analyzed primary causes, types, and costs of hospitalizations among 7,201 patients with chronic kidney disease (CKD) from renal speciality clinics across Queensland, Australia, over an average follow-up of 3.54 years. The average annual cost per person was $9,060, and was the highest in those with more advanced CKD, higher age, and with diabetes. More than 85% of costs were driven by more complex hospitalizations with longer length of stay. Cardiovascular disease was the single largest contributor for hospitalizations, length of hospital stay, and total costs. Readmission within 30 days of discharge, particularly for the same disorder, and multiday admissions should be the main targets for mitigation of hospital costs in this population.

Spatial Transcriptomics in Kidney Tissue.

Unlike bulk and single-cell/single-nuclei RNA sequencing methods, spatial transcriptome sequencing (ST-seq) resolves transcriptome expression within the spatial context of intact tissue. This is achieved by integrating histology with RNA sequencing. These methodologies are completed sequentially on the same tissue section placed on a glass slide with printed oligo-dT spots, termed ST-spots. Transcriptomes within the tissue section are captured by the underlying ST-spots and receive a spatial barcode in the process. The sequenced ST-spot transcriptomes are subsequently aligned with the hematoxylin and eosin (H&E) image, giving morphological context to the gene expression signatures within intact tissue. We have successfully employed ST-seq to characterize mouse and human kidney tissue. Here, we describe in detail the application of Visium Spatial Tissue Optimization (TO) and Visium Spatial Gene Expression (GEx) protocols for ST-seq in fresh frozen kidney tissue.

The Impact of Anaemia on Outcomes, Admissions, and Costs in Patients with Chronic Kidney Disease in Two Public Nephrology Practices in Queensland: A CKD.QLD Registry Study.

Aim: Anaemia among patients with chronic kidney disease (CKD) leads to poor overall outcomes. This study explores anaemia and its impact on nondialysis CKD (NDD-CKD) patients. Methods: 2,303 adults with CKD from two CKD.QLD Registry sites were characterised at consent and followed until start of kidney replacement therapy (KRT), death, or censor date. Mean follow-up was 3.9 (SD 2.1) years. Analysis explored the impact of anaemia on death, KRT start, cardiovascular events (CVE), admissions, and costs in these NDD-CKD patients. Results: At consent, 45.6% patients were anaemic. Males were more often anaemic (53.6%) than females, and anaemia was significantly more common over the age of 65 years. The prevalence of anaemia was highest among CKD patients with diabetic nephropathy (27.4%) and renovascular disease (29.2%) and lowest in patients with genetic renal disease (3.3%). Patients with admissions for gastrointestinal bleeding had more severe anaemia, but accounted for only the minority of cases overall. Administration of ESAs, iron infusions, and blood transfusions were all correlated with more severe degrees of anaemia. The number of hospital admissions, length of stay, and hospital costs were all strikingly higher with more severe degrees of anaemia. Adjusted hazard ratios (CI 95%) of patients with moderate and severe anaemia vs. no anaemia for subsequent CVE, KRT, and death without KRT were 1.7 (1.4-2.0), 2.0 (1.4-2.9), and 1.8 (1.5-2.3), respectively. Conclusion: Anaemia is associated with higher rates of CVE, progression to KRT and death in NDD- CKD patients, and with greater hospital utilisation and costs. Preventing and treating anaemia should improve clinical and economic outcomes.

Serum Creatinine and Tacrolimus Assessment With VAMS Finger-Prick Microsampling: A Diagnostic Test Study.

Rationale & Objective: Kidney transplant recipients require frequent venipunctures. Microsampling methods that use a finger-prick draw of capillary blood, like volumetric absorptive microsamplers (VAMS), have the potential to reduce the pain, inconvenience, and volume of blood loss associated with venipuncture. This study aimed to provide diagnostic accuracy using VAMS for measurement of tacrolimus and creatinine compared to gold standard venous blood in adult kidney transplant recipients. Study Design: Diagnostic test study. Prospective blood samples for measurement of tacrolimus and creatinine were collected using Mitra VAMS and venipuncture immediately before and 2 hours after tacrolimus dosing. Setting & Participants: A convenience sample of 40 adult kidney transplant participants in the outpatient setting. Tests Compared: Method comparison was assessed by Passing-Bablok regression and Bland-Altman analysis. The predictive performance of VAMS measurement compared to venipuncture was also assessed through estimation of the median prediction error and median absolute percentage prediction error. Results: A total of 74 tacrolimus samples and 70 creatinine samples were analyzed from 40 participants. Passing-Bablok regression showed a systematic difference between VAMS and venipuncture when measuring tacrolimus and creatinine with a slope of 1.08 (95% CI, 1.03-1.13) and a slope of 0.65 (95% CI, 0.6-0.7), respectively. These values were then corrected for the systematic difference. When used for Bland-Altman analysis, corrected values of tacrolimus and creatinine showed a bias of -0.1 µg/L and 0.04 mg/dL, respectively. Tacrolimus (corrected) and creatinine (corrected) microsampling values when compared to corresponding venipuncture values met median prediction error and median absolute percentage prediction error predefined acceptability limits of <15%. Limitations: This study was conducted in a controlled environment using a trained nurse to collect VAMS samples. Conclusions: In this study, VAMS was used to reliably measured tacrolimus and creatinine. This represents a clear opportunity for more frequent and less invasive sampling for patients.

Fingerprick Microsampling Methods Can Replace Venepuncture for Simultaneous Therapeutic Drug Monitoring of Tacrolimus, Mycophenolic Acid, and Prednisolone Concentrations in Adult Kidney Transplant Patients.

BACKGROUND: Kidney transplant patients undergo repeated and frequent venepunctures during allograft management. Microsampling methods that use a fingerprick draw of capillary blood, such as dried blood spots (DBS) and volumetric absorptive microsamplers (VAMS), have the potential to reduce the burden and volume of blood loss with venepuncture. METHODS: This study aimed to examine microsampling approaches for the simultaneous measurement of tacrolimus, mycophenolic acid, mycophenolic acid glucuronide (MPAG), and prednisolone drug concentrations compared with standard venepuncture in adult kidney transplant patients. DBS and VAMS were simultaneously collected with venepuncture samples from 40 adult kidney transplant patients immediately before and 2 hours after immunosuppressant dosing. Method comparison was performed using Passing-Bablok regression, and bias was assessed using Bland-Altman analysis. Drug concentrations measured through microsampling and venepuncture were also compared by estimating the median prediction error (MPE) and median absolute percentage prediction error (MAPE). RESULTS: Passing-Bablok regression showed a systematic difference between tacrolimus DBS and venepuncture [slope of 1.06 (1.01-1.13)] and between tacrolimus VAMS and venepuncture [slope of 1.08 (1.03-1.13)]. Tacrolimus values were adjusted for this difference, and the corrected values showed no systematic differences. Moreover, no systematic differences were observed when comparing DBS or VAMS with venepuncture for mycophenolic acid and prednisolone. Tacrolimus (corrected), mycophenolic acid, and prednisolone microsampling values met the MPE and MAPE predefined acceptability limits of <15% when compared with the corresponding venepuncture values. DBS and VAMS, collected in a controlled environment, simultaneously measured multiple immunosuppressants. CONCLUSIONS: This study demonstrates that accurate results of multiple immunosuppressant concentrations can be generated through the microsampling approach, with a preference for VAMS over DBS.

Cellular milieu in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC.

The 21st Century Cures Act: Perspectives of Clinicians in a Level-IV Neonatal Intensive Care Unit.

OBJECTIVE: Our objective is to describe the implications, anticipated and perceived, by providers in a level-IV neonatal intensive care unit (NICU) with immediate patient access to inpatient notes and test results in the wake of the 21st Century Cures Act (CCA). STUDY DESIGN: Using a mixed-method approach in February 2021, a preimplementation survey of neonatologists, neonatal fellows, nurse practitioners, and neonatal nurses reported their perspectives on the new 21st CCA and how they anticipated that it would change their practices, and the experience of families in the NICU. In the follow-up to implementation, a postsurvey was completed by staff reporting their experiences in July 2021. Thematic analysis was performed. RESULTS: In the preimplementation survey, staff reported the greatest perceived benefits of the changes to be an increase in families' ability to be part of the care team and prepare questions, and faster discussion of results by the care team. Also, staff's highest concerns were that family members may incorrectly interpret results delivered electronically without the context provided by the care team and be overwhelmed by the amount of information available. In the postimplementation survey, staff reported that the Act had less impact on their practice than they had anticipated preimplementation. CONCLUSION: To maximize benefits and limit burdens to families and staff, care teams should consider a thoughtful approach to information sharing with family members in compliance with the 21st CCA. KEY POINTS: · The impact of the 21 CCA on the NICU has not been studied.. · NICU staff have significant concerns related to the release of results to families.. · This study highlights the need to set expectations and provide family-centered care..

Chronic kidney disease in public renal practices in Queensland, Australia, 2011-2018.

AIM: To describe adults with (non-dialysis) chronic kidney disease (CKD) in nine public renal practice sites in the Australian state of Queensland. METHODS: 7,060 persons were recruited to a CKD Registry in May 2011 and until start of kidney replacement therapy (KRT), death without KRT or June 2018, for a median period of 3.4 years. RESULTS: The cohort comprised 7,060 persons, 52% males, with a median age of 68 yr; 85% had CKD stages 3A to 5, 45.4% were diabetic, 24.6% had diabetic nephropathy, and 51.7% were obese. Younger persons mostly had glomerulonephritis or genetic renal disease, while older persons mostly had diabetic nephropathy, renovascular disease and multiple diagnoses. Proportions of specific renal diagnoses varied >2-fold across sites. Over the first year, eGFR fell in 24% but was stable or improved in 76%. Over follow up, 10% started KRT, at a median age of 62 yr, most with CKD stages 4 and 5 at consent, while 18.8% died without KRT, at a median age of 80 yr. Indigenous people were younger at consent and more often had diabetes and diabetic kidney disease and had higher incidence rates of KRT. CONCLUSION: The spectrum of characteristics in CKD patients in renal practices is much broader than represented by the minority who ultimately start KRT. Variation in CKD by causes, age, site and Indigenous status, the prevalence of obesity, relative stability of kidney function in many persons over the short term, and differences between those who KRT and die without KRT are all important to explore.

Targeted biomarkers of progression in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is an increasingly significant health issue worldwide. Early stages of CKD can be asymptomatic and disease trajectory difficult to predict. Not every-one with CKD progresses to kidney failure, where kidney replacement therapy is the only life-sustaining therapy. Predicting which patients will progress to kidney failure would allow better use of targeted treatments and more effective allocation of health resources. Current diagnostic tests to identify patients with progressive disease perform poorly but there is a suite of new and emerging predictive biomarkers with great clinical promise. METHODS: This narrative review describes new and emerging biomarkers of pathophysiologic processes of CKD development and progression, accessible in blood or urine liquid biopsies. Biomarkers were selected based on their reported pathobiological functions in kidney injury, inflammation, oxidative stress, repair and fibrosis. Biomarker function and evidence of involvement in CKD development and progression are reported. CONCLUSION: Many biomarkers reviewed here have received little attention to date, perhaps because of conflicting conclusions of their utility in CKD. The functional roles of the selected biomarkers in the underlying pathobiology of progression of CKD are a powerful rationale for advancing and validating these molecules as prognosticators and predictors of CKD trajectory.

Hypoxic human proximal tubular epithelial cells undergo ferroptosis and elicit an NLRP3 inflammasome response in CD1c+ dendritic cells.

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O2) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c+ DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1ß and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1ß/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c+ DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD.

Pre-dialysis levels of inflammation and endotoxin in people receiving hemodialysis are not associated with blood pressure variability.

There are multiple risk factors for inflammation in dialysis. One potential cause is the presence of circulating levels of Gram-negative bacteria-derived endotoxin which is a strong inducer of inflammation. Gut-associated endotoxin may enter the circulation via a defective blood-gut barrier during episodes of hypotension or reduced perfusion. MATERIALS AND METHODS: In this study, 165 patients receiving outpatient-based hemodialysis in a facility (FHD) or at home (HHD), were studied. Levels of inflammation were quantified by developing an inflammatory score derived from the measurement of pro-inflammatory cytokines, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Intradialytic blood pressure (BP) variability and hypotension events were recorded. This included the final session of dialysis, at the commencement of which the blood samples were drawn, as well as the five preceding sessions. RESULTS: The median inflammatory score was 2 (range 0 - 3), and 30% of patients had an inflammatory score of three suggesting significant levels of inflammation. Only 8.5% had an inflammatory score of 0. Endotoxin was measured in all participants and was only positive in N = 3. The mean systolic blood pressure (SBP) was 134 ± 20 mmHg and the BP variability was 11.7 ± 3.5. In a multivariable ordinal regression model, a higher inflammatory score was significantly associated with younger age (OR 0.95, 95% CI 0.95 - 0.99, p = 0.03), higher ultrafiltration volume (OR 1.62, CI 1.04 - 2.54, p = 0.03) and lower body mass index (OR 0.9, CI 0.86 - 0.96, p = 0.01). There was no association between inflammatory score and dialysis modality, access type, kidney replacement therapy (KRT), BP variability, or endotoxin. Endotoxin was detected in only 3 of 165 patients and was not associated with inflammation. CONCLUSION: Pre-dialysis levels of inflammation are prevalent in the hemodialysis population after the long break but are not related to intradialytic BP variability or hypotension in the preceding 2 weeks. However, endotoxemia is uncommon and unlikely to be a significant driver of inflammation.

Spatially Resolved Transcriptomes of Mammalian Kidneys Illustrate the Molecular Complexity and Interactions of Functional Nephron Segments.

Available transcriptomes of the mammalian kidney provide limited information on the spatial interplay between different functional nephron structures due to the required dissociation of tissue with traditional transcriptome-based methodologies. A deeper understanding of the complexity of functional nephron structures requires a non-dissociative transcriptomics approach, such as spatial transcriptomics sequencing (ST-seq). We hypothesize that the application of ST-seq in normal mammalian kidneys will give transcriptomic insights within and across species of physiology at the functional structure level and cellular communication at the cell level. Here, we applied ST-seq in six mice and four human kidneys that were histologically absent of any overt pathology. We defined the location of specific nephron structures in the captured ST-seq datasets using three lines of evidence: pathologist's annotation, marker gene expression, and integration with public single-cell and/or single-nucleus RNA-sequencing datasets. We compared the mouse and human cortical kidney regions. In the human ST-seq datasets, we further investigated the cellular communication within glomeruli and regions of proximal tubules-peritubular capillaries by screening for co-expression of ligand-receptor gene pairs. Gene expression signatures of distinct nephron structures and microvascular regions were spatially resolved within the mouse and human ST-seq datasets. We identified 7,370 differentially expressed genes (p adj < 0.05) distinguishing species, suggesting changes in energy production and metabolism in mouse cortical regions relative to human kidneys. Hundreds of potential ligand-receptor interactions were identified within glomeruli and regions of proximal tubules-peritubular capillaries, including known and novel interactions relevant to kidney physiology. Our application of ST-seq to normal human and murine kidneys confirms current knowledge and localization of transcripts within the kidney. Furthermore, the generated ST-seq datasets provide a valuable resource for the kidney community that can be used to inform future research into this complex organ.

Cost-Effectiveness and Budget Impact Analysis of Implementing a 'Soft Opt-Out' System for Kidney Donation in Australia.

INTRODUCTION: There is a severe shortage of donor organs globally. There is growing interest in understanding how a 'soft opt-out' organ donation system could help bridge the supply and demand gap for donor organs. This research aims to estimate the cost-effectiveness and budget impact of implementing a 'soft opt-out' organ donation system for kidney donation. METHODS: A decision-analytic model was developed to estimate the incremental costs from a health system's perspective, quality-adjusted life-years (QALYs), and death averted of people who have kidney failure, comparing a 'soft opt-out' organ donation system to an 'opt-in' system. This study analysed three scenarios where the 'soft opt-out' system generated a 20%, 30%, and 40% increase in deceased organ donation rates over 20 years. A 5-year time horizon was adopted for the budget impact analysis. RESULTS: A 20% increase in organ donation rates could have a cost saving of 650 million Australian dollars (A$) and a 10,400-QALY gain. A 20% increase would avert more than 1500 deaths, while a 40% increase would avert 3200 deaths over a time horizon of 20 years. Over the first 5 years, a 20% increase would have a net saving of A$53 million, increasing to A$106 million if the donation rate increases by 40%. CONCLUSION: A 'soft opt-out' organ donation system would return a cost saving for the healthcare system, a net gain in QALYs, and prevention of a significant number of deaths. Advantageous budgetary impact is important, but understanding the aversion for a 'soft opt-out' system in Australia is also important and remains a priority for further research.

The prevalence of Fabry disease in a statewide chronic kidney disease cohort - Outcomes of the aCQuiRE (Ckd.Qld fabRy Epidemiology) study.

BACKGROUND: Prevalence of Fabry disease amongst Chronic Kidney Disease (CKD) patients on haemodialysis has been shown to be approximately 0.2%. METHODS: We undertook a cross-sectional study employing a cascade screening strategy for Fabry Disease amongst 3000 adult, male and female patients affected by CKD stage 1-5D/T at public, specialty renal practices within participating Queensland Hospital and Health Services from October 2017 to August 2019. A multi-tiered FD screening strategy, utilising a combination of dried blood spot (DBS) enzymatic testing, and if low, then lyso-GB3 testing and DNA sequencing, was used. RESULTS: Mean (SD) age was 64.0 (15.8) years (n = 2992), and 57.9% were male. Eight participants withrew out of the 3000 who consented. Of 2992 screened, 6 (0.20%) received a diagnosis of FD, 2902 (96.99%) did not have FD, and 84 (2.81%) received inconclusive results. Of the patients diagnosed with FD, mean age was 48.5 years; 5 were male (0.29%) and 1 was female (0.08%); 4 were on kidney replacement therapy (2 dialysis and 2 transplant); 3 were new diagnoses. CONCLUSIONS: Estimated overall FD prevalence was 0.20%. Screening of the broader CKD population may be beneficial in identifying cases of FD. TRIAL REGISTRATION: The aCQuiRE Study has been prospectively registered with the Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au ) as pj09946 (Registered 3rd July 2017).