Hotspots of kidney failure: Analysing Australian metropolitan dialysis demand for service planning.

OBJECTIVE: To locate incident hotspots of dialysis demand in Australian capital cities and measure association with prevalent dialysis demand and socioeconomic disadvantage. METHODS: A retrospective cohort study used Australia and New Zealand Dialysis and Transplant Registry data on people commencing dialysis for kidney failure (KF) resident in an Australian capital city, 1 January 2001 - 31 December 2021. Age-sex-standardised dialysis incidence was estimated by Statistical Area Level 3 (SA3) and dialysis prevalence by SA2. RESULTS: A total of 32,391 people commencing dialysis were referenced to SA3s within city metropolitan areas based on residential postcode. Incident hotspots were located in Western Sydney. The highest average annual change of standardised incidence was 8.3 per million people (false discovery rate-corrected 95% CI 1.0,15.7) in Mount Druitt, reflecting a 263% increase in absolute demand from 2001-3 to 2019-21. Incident dialysis for diabetic kidney disease contributed substantially to total growth. Incident hotspots were co-located with areas where prevalent dialysis demand was associated with socioeconomic deprivation. CONCLUSIONS: Novel spatial analyses of geo-referenced registry data located hotspots of kidney failure and associated socio-demographic and comorbid states. IMPLICATIONS FOR PUBLIC HEALTH: These analyses advance current abilities to plan dialysis capacity at a local level. Hotspots can be targeted for prevention and slowing the progression of kidney disease.

Greater haemodialysis exposure ('quotidian haemodialysis') has different mortality associations by patient age group.

Background: Worldwide, most people requiring kidney replacement therapy receive haemodialysis (HD) three times per week. Greater HD time and/or frequency may improve survival, but implementation requires understanding potential benefits across the range of patients. Methods: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we assessed whether quotidian HD (defined as >3 sessions/week and/or >5 h/session) was associated with reduced mortality in adult patients. The primary outcome of all-cause mortality was analysed by a time-varying Cox proportional hazards model with quotidian HD as the exposure of interest. Results: Of 24 138 people who received HD between 2011 and 2019, 2632 (10.9%) received quotidian HD at some stage. These patients were younger, more likely male and more likely to receive HD at home. Overall, quotidian versus standard HD was associated with a decreased risk for all-cause mortality {crude hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.45-0.56]}, but an interaction between quotidian HD and age was identified (P = .005). Stratified by age groups and splitting follow-up time where proportional hazards were violated, the corresponding HR compared with standard HD was 2.43 (95% CI 1.56-3.79) for people >75 years of age in the first year of quotidian HD, 1.52 (95% CI 0.89-2.58) for 1-3 years and 0.95 (95% CI 0.51-1.78) for ≥3 years. There was no significant survival advantage in younger people. Conclusions: Although quotidian HD conferred survival benefit in crude analyses, people ≥75 years of age had greater mortality with quotidian HD than standard HD. The mortality benefit in younger people was attenuated when adjusted for known confounders.

Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications.

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma.

Calciphylaxis Episodes in the Australia and New Zealand Dialysis and Transplant Registry.

Introduction: Calciphylaxis is a rare disorder associated with significant morbidity and mortality. Data registries are an invaluable source of information for rare diseases. We reviewed cases of calciphylaxis recorded in the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and evaluated associations and outcomes of this condition. Methods: Data was obtained on all cases of calciphylaxis reported between 2019 and 2022 in Australian and New Zealand patients on kidney replacement therapy (KRT). This cohort was compared to all patients in the registry who received KRT from 2019 to 2022 without an episode of calciphylaxis. Cox proportional hazards regression including a time-varying covariate for calciphylaxis episode was conducted for mortality with models restricted to patients on dialysis only. Results: From 2019 to 2022, 333 patients had calciphylaxis episodes reported. Overall incidence rate for patients on dialysis was 4.5 (4.1-5.1) episodes per 1000 patient-years on dialysis. Median age was 63 (interquartile range [IQR]: 55-73) years, 54% were female, 66% had diabetes, 59% were obese (body mass index [BMI] ≥ 30 kg/m2) and 77% were receiving hemodialysis (HD) treatment. Compared to patients without calciphylaxis (n = 46,526), patients with calciphylaxis were more likely to be older, female, and have diabetes, greater BMI, coronary artery, and peripheral vascular disease. The median time to calciphylaxis was 3.2 (IQR: 0.9-6.7) years after KRT commencement. Half of the patients with calciphylaxis died by 12 months from diagnosis. Adjusted hazard ratio (HR) of mortality for patients on dialysis with calciphylaxis <1 year and 1 to 4 years after an episode was 5.8 (4.9-6.9) and 1.5 (1.0-2.1), respectively compared to patients on dialysis without calciphylaxis. Conclusion: Calciphylaxis is a rare but life-threatening condition in people on KRT with the greatest mortality burden within 12 months of diagnosis.

Patient Perspectives of Center-Specific Reporting in Kidney Failure Care: An Australian Qualitative Study.

Introduction: Public reporting of quality of care indicators in healthcare is intended to inform consumer decision-making; however, people may be unaware that such information exists, or it may not capture their priorities. The aim of this study was to understand the views of people with kidney disease about public reporting of dialysis and transplant center outcomes. Methods: This qualitative study involved 27 patients with lived experience of kidney disease in Australia who participated in 11 online focus groups between August and December 2022. Transcripts were analyzed thematically. Results: Patients from all Australian states and territories participated, with 22 (81%) having a functioning kidney transplant and 22 (81%) having current or previous experience of dialysis. Five themes were identified as follows: (i) surrendering to the health system, (ii) the complexity of quality, (iii) benefits for patient care and experience, (iv) concerned about risks and unintended consequences, and (v) optimizing the impact of data. Conclusion: Patients desire choice among kidney services but perceive this as rarely possible in the Australian context. Health professionals are trusted to make decisions about appropriate centers. Public reporting of center outcomes may induce fear and a loss of balanced perspective; however, it was supported by all participants and represents an opportunity for self-advocacy and informed decision-making. Strategies to mitigate potential risks include availability of trusted clinicians and community members to aid in data interpretation, providing context about centers and patients, and framing statistics to promote positivity and hope.

Antecedent Cardiac Arrest Status of Donation After Circulatory Determination of Death (DCDD) Kidney Donors and the Risk of Delayed Graft Function After Kidney Transplantation: A Cohort Study.

BACKGROUND: The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF). METHODS: Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF. RESULTS: A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF. CONCLUSIONS: This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest.

Association between diabetic status and risk of all-cause and cause-specific mortality on dialysis following first kidney allograft loss.

Background: Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods: All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results: Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1-5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17-1.84) and 1.47 (1.23-1.76), respectively; for CVD-related mortality were 0.81 (0.51-1.29) and 1.02 (0.70-1.47), respectively; for infection-related mortality were 1.84 (1.02-3.35) and 2.70 (1.73-4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05-2.77) and 1.51 (1.02-2.22), respectively. Conclusions: Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal.

Ureidopenicillins Are Potent Inhibitors of Penicillin-Binding Protein 2 from Multidrug-Resistant Neisseria gonorrhoeae H041.

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido ß-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R1 group. Crystal structures show that the ureido ß-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of ß-lactams with improved activity against ESC-resistant N. gonorrhoeae.

Associations of neutral pH, low-GDP peritoneal dialysis solutions with patient survival, transfer to haemodialysis and peritonitis.

BACKGROUND: Peritoneal dialysis (PD) solutions containing low levels of glucose degradation products (GDPs) are associated with attenuation of peritoneal membrane injury and vascular complications. However, clinical benefits associated with neutral-pH, low-GDP (N-pH/L-GDP) solutions remain unclear. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the associations between N-pH/L-GDP solutions and all-cause mortality, cause-specific mortality, transfer to haemodialysis (HD) for ≥30 days and PD peritonitis in adult incident PD patients in Australia and New Zealand between 1 January 2005 and 31 December 2020 using adjusted Cox regression analyses. RESULTS: Of 12 814 incident PD patients, 2282 (18%) were on N-pH/L-GDP solutions. The proportion of patients on N-pH/L-GDP solutions each year increased from 11% in 2005 to 33% in 2017. During the study period, 5330 (42%) patients died, 4977 (39%) experienced transfer to HD and 5502 (43%) experienced PD peritonitis. Compared with the use of conventional solutions only, the use of any form of N-pH/L-GDP solution was associated with reduced risks of all-cause mortality {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]}, cardiovascular mortality [aHR 0.65 (95% CI 0.56-0.77)], infection-related mortality [aHR 0.62 (95% CI 0.47-0.83)] and transfer to HD [aHR 0.79 (95% CI 0.72-0.86)] but an increased risk of PD peritonitis [aHR 1.16 (95% CI 1.07-1.26)]. CONCLUSIONS: Patients who received N-pH/L-GDP solutions had decreased risks of all-cause and cause-specific mortality despite an increased risk of PD peritonitis. Studies assessing the causal relationships are warranted to determine the clinical benefits of N-pH/L-GDP solutions.

Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial.

BACKGROUND: Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes. METHODS: The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV1/forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [≥2%] or placebo if eosinophil count was low [<2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete. FINDINGS: Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46-84] and mean percent predicted FEV1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33-1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study. INTERPRETATION: Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice. FUNDING: National Institute for Health and Care Research.

Application of N-Terminal Site-Specific Biotin and Digoxigenin Conjugates to Clinical Anti-drug Antibody Assay Development.

Biotin- and digoxigenin (DIG)-conjugated therapeutic drugs are critical reagents used for the development of anti-drug antibody (ADA) assays for the assessment of immunogenicity. The current practice of generating biotin and DIG conjugates is to label a therapeutic antibody with biotin or DIG via primary amine groups on lysine or N-terminal residues. This approach modifies lysine residues nonselectively, which can impact the ability of an ADA assay to detect those ADAs that recognize epitopes located at or near the modified lysine residue(s). The impact of the lysine modification is considered greater for therapeutic antibodies that have a limited number of lysine residues, such as the variable heavy domain of heavy chain (VHH) antibodies. In this paper, for the first time, we report the application of site-specifically conjugated biotin- and DIG-VHH reagents to clinical ADA assay development using a model molecule, VHHA. The site-specific conjugation of biotin or DIG to VHHA was achieved by using an optimized reductive alkylation approach, which enabled the majority of VHHA molecules labeled with biotin or DIG at the desirable N-terminus, thereby minimizing modification of the protein after labeling and reducing the possibility of missing detection of ADAs. Head-to-head comparison of biophysical characterization data revealed that the site-specific biotin and DIG conjugates demonstrated overall superior quality to biotin- and DIG-VHHA prepared using the conventional amine coupling method, and the performance of the ADA assay developed using site-specific biotin and DIG conjugates met all acceptance criteria. The approach described here can be applied to the production of other therapeutic-protein- or antibody-based critical reagents that are used to support ligand binding assays.

Association between major histocompatibility complex haplotypes and susceptibility of unvaccinated and vaccinated cattle to paratuberculosis.

Bovine Johne's disease (BJD) or paratuberculosis is caused by Mycobacterium avium spp. paratuberculosis (MAP) and is a worldwide problem among domestic and wild ruminants. While vaccines are available, natural differences in background immunity between breeds within species and between individuals within herds suggest that genetic differences may be able to be exploited in marker-assisted selection as an aid to disease control. The major histocompatibility complex (MHC) is an important component in immune recognition with considerable genetic variability. In this study, associations between the MHC and resistance to BJD were explored in dairy cattle across two herds in which some of the cattle had been vaccinated with Silirum® (n = 540 cows). A BJD susceptible animal was exposed to MAP and became infected, while a resistant animal was exposed but did not become infected. There are different ways to define both exposure and infection, with different levels of stringency, therefore many classifications of the same set of animals are possible and were included in the analysis. The polymorphic regions of major histocompatibility complex class I (MHC I) and class II (MHC II) genes were amplified from the genomic DNA by PCR and sequenced, targeting exons 2 and 3 of the classical and non-classical MHC I genes and exon 2 from the DRB3, DQA1, DQA2 + 3 and DQB MHC II genes. The frequencies of MHC I and MHC II haplotypes and alleles were determined in susceptible and resistant populations. In unvaccinated animals, seven MHC I haplotypes and seven MHC II haplotypes were associated with susceptibility while two MHC I and six MHC II haplotypes were associated with resistance (P < 0.05). In vaccinated animals, two MHC I and three MHC II haplotypes were associated with susceptibility, while one MHC I and two MHC II haplotypes were associated with resistance (P < 0.05). The alleles in significant haplotypes were also identified. Case definitions with higher stringency resulted in fewer animals being included in the analyses, but the power to detect an association was not reduced and there was an increase in strength and consistency of associations. Consistent use of stringent case definitions is likely to improve agreement in future association studies.

Donors With a Prior History of Cancer: Factors of Non-Utilization of Kidneys for Transplantation.

Cancer transmission from deceased donors is an exceedingly rare but potentially fatal complication in transplant recipients. We aimed to quantify the likelihood of non-utilization of kidneys for transplantation from donors with a prior cancer history. We included all intended and actual deceased donors in Australia and New Zealand between 1989 and 2017. Association between prior cancer history and non-utilization of donor kidneys was examined using adjusted logistic regression. Of 9,485 deceased donors, 345 (4%) had a prior cancer history. Of 345 donors with a prior cancer history, 197 (57%) were utilized for transplantation. Donor characteristics of age, sex and comorbidities were similar between utilized and non-utilized donors with prior cancer. The time from cancer to organ donation was similar between utilized and non-utilized donors, irrespective of cancer subtypes. Donors with a prior cancer history were less likely to be utilized [adjusted OR (95% CI) 2.29 (1.68-3.13)] than donors without prior cancer. Of all actual donors, the adjusted OR for non-utilization among those with prior cancer was 2.36 (1.58-3.53). Non-melanoma skin cancer was the most frequent prior cancer type for utilized and non-utilized potential donors. Donors with prior cancers were less likely to be utilized for transplantation, with no discernible differences in cancer characteristics between utilized and non-utilized donors.

Loss of Diel Circadian Clock Gene Cycling Is a Part of Grape Berry Ripening.

Diel cycles of gene expression are thought to adapt plants to 24-h changes in environmental conditions. The circadian clock contributes to this process, but less is known about circadian programs in developing reproductive organs. While model plants and controlled conditions have contributed greatly to our knowledge of circadian clock function, there is a need to better understand its role in crop plants under field conditions with fluctuating light and temperature. In this study, we investigated changes in the circadian clock during the development of grape berries of Vitis vinifera L. We found that the transcripts of circadian clock homologs had high-amplitude oscillations prior to, but not during, ripening. As ripening progressed, the amplitude and rhythmicity of the diel oscillations decreased until most transcripts tested had no significant fluctuation over the 24-h cycle. Despite this loss of rhythmicity, the majority of circadian clock genes investigated were expressed at or near their abundance at the nadir of their pre-ripening oscillation although the berries remained transcriptionally active. From this, it can be concluded that cycling of the canonical circadian clock appears unnecessary for berry ripening. Our data suggest that changes in circadian clock dynamics during reproductive organ development may have important functional consequences.

Complete loss of TP53 and RB1 is associated with complex genome and low immune infiltrate in pleomorphic rhabdomyosarcoma.

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. Lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic, and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration.

Parenthood in people with kidney failure: evolution and evaluation of completeness of ANZDATA registry parenthood data.

BACKGROUND: Parenthood data has been collected by the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) since its inception in 1968, with a specific parenthood survey since 2001 of core maternal and fetal outcomes, which was further expanded in 2017 to collect additional obstetric and clinical data. We evaluated the parenthood dataset completeness over the evolution of the surveys. METHODS: Descriptive statistics were used to quantify the completeness of data reported for male and female patients receiving KRT between 1963 and 2021 and compare parenthood surveys over time. RESULTS: Core data items consistently had more than 85% completeness rates for all survey iterations. Most data items introduced in 2018 had less than 85% completeness. Of these, drug therapy during pregnancy, common medical complications, and labour and delivery data items had the highest completeness (70-85%), whereas dialysis-related items had a wide range of completeness, ranging from 44 to 80%. CONCLUSION: Our findings underpin the robustness of the ANZDATA parenthood dataset but also highlight that more detailed clinical data can be difficult to capture, despite enabling better understanding of drivers of outcomes and risk stratification in this high-risk cohort. To overcome current limitations, strategies must be implemented to augment data completeness.

Trajectories of systolic blood pressure decline in kidney transplant donors prior to circulatory death and delayed graft function.

Background: Kidneys donated after circulatory death suffer a period of functional warm ischaemia before death, which may lead to early ischaemic injury. Effects of haemodynamic trajectories during the agonal phase on delayed graft function (DGF) is unknown. We aimed to predict the risk of DGF using patterns of trajectories of systolic blood pressure (SBP) declines in Maastricht category 3 kidney donors. Methods: We conducted a cohort study of all kidney transplant recipients in Australia who received kidneys from donation after circulatory death donors, divided into a derivation cohort (transplants between 9 April 2014 and 2 January 2018 [462 donors]) and a validation cohort (transplants between 6 January 2018 and 24 December 2019 [324 donors]). Patterns of SBP decline using latent class models were evaluated against the odds of DGF using a two-stage linear mixed effects model. Results: In the derivation cohort, 462 donors were included in the latent class analyses and 379 donors in the mixed effects model. Of the 696 eligible transplant recipients, 380 (54.6%) experienced DGF. Ten different trajectories, with distinct patterns of SBP decline were identified. Compared with recipients from donors with the slowest decline in SBP after withdrawal of cardiorespiratory support, the adjusted odds ratio (aOR) for DGF was 5.5 [95% confidence interval (CI) 1.38-28.0] for recipients from donors with a steeper decline and lowest SBP [mean 49.5 mmHg (standard deviation 12.5)] at the time of withdrawal. For every 1 mmHg/min reduction in the rate of decline of SBP, the respective aORs for DGF were 0.95 (95% CI 0.91-0.99) and 0.98 (95% CI 0.93-1.0) in the random forest and least absolute shrinkage and selection operator models. In the validation cohort, the respective aORs were 0.95 (95% CI 0.91-1.0) and 0.99 (95% CI 0.94-1.0). Conclusion: Trajectories of SBP decline and their determinants are predictive of DGF. These results support a trajectory-based assessment of haemodynamic changes in donors after circulatory death during the agonal phase for donor suitability and post-transplant outcomes.

Long-term Trends in Infection-Related Mortality in Adults Treated With Maintenance Dialysis.

RATIONALE & OBJECTIVE: Infection is 1 of the top 3 causes of death in patients receiving maintenance dialysis. We evaluated the trends over time and risk factors for infection-related deaths among people receiving dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We included all adults who began dialysis between 1980 and 2018 in Australia and New Zealand. EXPOSURE: Age, sex, dialysis modality, and dialysis era. OUTCOME: Infection-related death. ANALYTICAL APPROACH: Incidence was described and standardized mortality ratios (SMR) calculated for infection-related death. Fine-Gray subdistribution hazards models were fitted, with non-infection-related death and kidney transplantation treated as competing events. RESULTS: The study comprised 46,074 patients who received hemodialysis and 20,653 who were treated with peritoneal dialysis who were followed for 164,536 and 69,846 person-years, respectively. There were 38,463 deaths during the follow-up period, 12% of which were ascribed to infection. The overall rate of mortality from infection (per 10,000 person-years) was 185 and 232 for patients treated with hemodialysis and peritoneal dialysis, respectively. The rates were 184 and 219 for males and females, respectively; and 99, 181, 255, and 292 for patients aged 18-44, 45-64, 65-74, 75 years and over, respectively. The rates were 224 and 163 for those commencing dialysis in years 1980-2005 and 2006-2018, respectively. The overall SMR declined over time, from 37.1 (95% CI, 35.5-38.8) in years 1980-2005 to 19.3 (95% CI, 18.4-20.3) in years 2006-2018, consistent with the declining 5-year SMR trend (P<0.001). Infection-related mortality was associated with being female, older age, and Aboriginal and/or a Torres Strait Islander or Maori. LIMITATIONS: Mediation analyses defining the causal relationships between infection type and infection-related death could not be undertaken as disaggregating the data was not feasible. CONCLUSIONS: The excess risk of infection-related death in patients on dialysis has improved substantially over time but remains more than 20 times higher than in the general population.

Subclassification of epithelioid sarcoma with potential therapeutic impact.

Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1-deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1-deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1-deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1-deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8+ lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Discovery of a novel transcriptional regulator of sugar catabolism in archaea.

The haloarchaeon Haloferax volcanii degrades D-glucose via the semiphosphorylative Entner-Doudoroff pathway and D-fructose via a modified Embden-Meyerhof pathway. Here, we report the identification of GfcR, a novel type of transcriptional regulator that functions as an activator of both D-glucose and D-fructose catabolism. We find that in the presence of D-glucose, GfcR activates gluconate dehydratase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase and also acts as activator of the phosphotransferase system and of fructose-1,6-bisphosphate aldolase, which are involved in uptake and degradation of D-fructose. In addition, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase are activated by GfcR in the presence of D-fructose and also during growth on D-galactose and glycerol. Electrophoretic mobility shift assays indicate that GfcR binds directly to promoters of regulated genes. Specific intermediates of the degradation pathways of the three hexoses and of glycerol were identified as inducer molecules of GfcR. GfcR is composed of a phosphoribosyltransferase (PRT) domain with an N-terminal helix-turn-helix motif and thus shows homology to PurR of Gram-positive bacteria that is involved in the transcriptional regulation of nucleotide biosynthesis. We propose that GfcR of H. volcanii evolved from a PRT-like enzyme to attain a function as a transcriptional regulator of central sugar catabolic pathways in archaea.