Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Background Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. Methods People aged 0–96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan–Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). Findings Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9–16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32–0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Interpretation Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3–5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. Funding RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo.BackgroundErythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is known to be up-regulated during states of hypoxia. Here we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal dysfunction and injury with recombinant human EPO in mice when given as either a 3-day pretreatment, or upon reperfusion of the kidney.MethodsMice were treated with EPO (1000 IU/kg/day subcutaneously) for 3 days, or treated with EPO (1000 IU/kg subcutaneously) upon reperfusion, and subsequently subjected to bilateral renal artery occlusion (30 minutes) and reperfusion (24 hours). At the end of experiments, the following indicators and markers of renal injury and dysfunction were measured: plasma urea, creatinine, and aspartate aminotransferase (AST), tissue myeloperoxidase (MPO) activity [for polymorphonuclear leukocyte (PMN) infiltration], and tissue malonaldehyde (MDA) levels (for tissue lipid peroxidation). Kidneys were used for histologic evaluation of renal injury.ResultsEPO was able to significantly attenuate the renal dysfunction and injury associated with I/R, as well as the tissue injury. The increase in renal MPO activity and, hence, the degree of PMN infiltration were also significantly reduced in EPO-treated mice. In addition, lipid peroxidation as a result of renal I/R injury was also attenuated in EPO-treated mice.ConclusionThe protection afforded by the pretreatment regime of EPO was greater than that of administering EPO as a single bolus upon reperfusion. We propose that different mechanisms underlie the protective effects seen with EPO when given as either a daily pretreatment or as a single bolus, which need to be further investigated

Supplementary Material for: Outcomes of Elderly Patients with Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis Treated with Immunosuppressive Therapy

<i>Background/Aims:</i> Anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is a cause of biopsy-proven acute kidney injury, more common in the elderly. Treatment requires immunosuppression, which can have significant toxic effects. The aim of this study was to assess whether morbidity and mortality that are associated with immunosuppression for AAV varied with age. <i>Methods:</i> A retrospective review of 232 patients given induction therapy with prednisolone and cyclophosphamide was conducted. Information was collected on baseline characteristics (including requirement for dialysis at presentation) and the occurrence of leukopenia, infection, end-stage renal disease and death during follow-up. <i>Results:</i> Median follow-up was 51 months. Older patients (aged ≥70 years) were treated with lower total cyclophosphamide doses than those aged <70 years (mean 7.3 g (SD 4.4) vs. 10.7 g (SD 7.4), respectively). Increasing age was associated with an increased risk of leukopenia (odds ratio (OR) 1.50; 95% confidence interval (CI) 1.20-1.86; p < 0.001), and older patients were more likely to develop infections in the first year (OR 1.87; 95% CI 1.1-3.2). Older patients were also significantly more likely to require dialysis at presentation (OR 1.66; 95% CI 1.13-2.5) and longer term. After multivariable adjustment, age and requirement for dialysis at presentation were significant predictors of death (hazard ratio (HR) per year of age 1.07; 95% CI 1.03-1.11; p < 0.001 and HR 2.2; 95% CI 1.10-4.38; p = 0.03, respectively). <i>Conclusions:</i> Among patients treated with prednisolone and cyclophosphamide, increasing age and dialysis dependency were associated with worse survival. Older patients were more likely to develop treatment-related complications despite lower cumulative doses of immunosuppression. Morbidity and mortality associated with treatment must therefore be carefully balanced against that associated with the disease process itself

Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes

In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, alpha-actinin-4 and talin-1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin-1 is a specific proteolytic target of calpain-1, we investigated a potential trigger of calpain activation and talin-1 degradation using human ex vivo precision-cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain-1 by transforming growth factor-beta generated proteolytic fragments of talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain-1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies

On the process and outcomes of inquiry learning: Changing approaches to assessment

Inquiry learning is an educational approach that involves a process of exploration, asking questions and making discoveries in the search for new understandings. Researchers however are divided about the value of the approach. In the symposium, it is argued that one of the reasons for this controversy is the way that inquiry learning is assessed. Consequently, we aim to present papers which reflect on the challenge of assessing inquiry learning by describing the prevailing approaches to assessment and how technological and theoretical advancement is changing these approaches. The aim is not just to describe these approaches but reflect upon the opportunities that are created and difficulties that must be overcome as we pursue the goal of assessing the processes and outcomes of inquiry learnin

Mobile Collaboration for Language Learning and Cultural Learning

Locations outside the classroom represent social spaces or “settings” that offer a variety of affordances for language learning, but these opportunities will not be fully realized unless we make efforts to propose and try out new designs for learning in these settings. It is especially important to consider how learners might assemble, configure or help create learning designs that involve mobile technologies, tasks and resources corresponding to their needs, in readiness for chance encounters and for more sustained learning. Two key questions are pertinent to the issues outlined above when considering the nexus of collaboration, cultural experiences, and the interface between formal and informal learning: (1) What are the key findings from research studies and reported experiences of collaboration in mobile language learning, with particular reference to informal settings and cultural learning? (2) What do these findings mean for teacher roles, and how can learners be supported and developed to engage more effectively in collaborative and cultural mobile language learning? These two broad questions set the scene for this chapter and guide its structure. In the first part, we focus on existing studies to examine what has been tried and to establish the key findings. The existing studies include some in which we have been involved, often as lead researchers. After that, we consider teachers’ and learners’ changing roles and the foregrounding or development of competencies and skills that are important for more informal, and perhaps increasingly collaborative, mobile language learning. In the conclusion we propose a list of five areas of focus for teachers and learners to become aware that language learning with mobiles can operate across a highly‐flexible continuum from informal to formal learning and intercultural exchange

The Angular Momentum Distribution and Baryon Content of Star-forming Galaxies at z ~ 1-3

We analyze the angular momenta of massive star-forming galaxies (SFGs) at the peak of the cosmic star formation epoch (z ~ 0.8–2.6). Our sample of ~360 log(M */M ⊙) ~ 9.3–11.8 SFGs is mainly based on the KMOS3D and SINS/zC-SINF surveys of Hα kinematics, and collectively provides a representative subset of the massive star-forming population. The inferred halo scale angular momentum distribution is broadly consistent with that theoretically predicted for their dark matter halos, in terms of mean spin parameter $\langle \lambda \rangle$ ~ 0.037 and its dispersion (σ logλ ~ 0.2). Spin parameters correlate with the disk radial scale and with their stellar surface density, but do not depend significantly on halo mass, stellar mass, or redshift. Our data thus support the long-standing assumption that on average, even at high redshifts, the specific angular momentum of disk galaxies reflects that of their dark matter halos (j d = j DM). The lack of correlation between λ × (j d /j DM) and the nuclear stellar density Σ*(1 kpc) favors a scenario where disk-internal angular momentum redistribution leads to "compaction" inside massive high-redshift disks. For our sample, the inferred average stellar to dark matter mass ratio is ~2%, consistent with abundance matching results. Including the molecular gas, the total baryonic disk to dark matter mass ratio is ~5% for halos near 1012 M ⊙, which corresponds to 31% of the cosmologically available baryons, implying that high-redshift disks are strongly baryon dominated