Studying glomerular disease epidemiology: tackling challenges and paving a path forward

Background: Glomerular diseases are a group of rare immune-mediated kidney diseases that affect the glomeruli, or filtering units, of the kidney. Major knowledge gaps remain in our understanding of glomerular disease epidemiology. Efforts to describe glomerular disease distributions based on geographic, demographic, and temporal factors (descriptive epidemiology) are limited by the absence of population-level disease registries in most jurisdictions. The extent to which glomerular disease subtype independently associates with clinical outcomes (analytic epidemiology), especially once kidney disease has progressed to end-stage kidney failure, remains largely unknown. Further, much of what is known regarding glomerular disease epidemiology is derived from the experiences of highly-selected patient populations enrolled in clinical trials or attending academic medical centres. Larger-scale, population-level, studies of glomerular disease epidemiology would help to close knowledge gaps regarding the distribution and determinants of glomerular disease and, in doing so, would inform clinical care, public health policy, and clinical trial design. Hypotheses: Two major hypotheses are explored in this thesis: 1. Significant geographic and temporal variation in glomerular disease frequencies exist, that are not solely explained by racial-ethnic variation, thus supporting a role for socioeconomic and environmental factors in the development of clinically manifest glomerular disease; 2. Glomerular disease subtype independently associates with clinical outcomes even after glomerular disease has advanced to end-stage kidney failure, challenging the prevailing paradigm to group all glomerular disease subtypes together in research and public health reporting of clinical outcomes in patients with end-stage kidney failure. Aims: The overall aim of this research was to close knowledge gaps in glomerular disease epidemiology by identifying geographic and temporal variation in glomerular disease frequency distributions and by determining associations between glomerular disease subtype and clinical outcomes (mortality, cardiovascular events) in patients with end-stage kidney failure. Methods: For the first two manuscripts (Chapters 3 and 4), I analysed two large-scale pathology datasets created by my collaborator, Dr. Charles Jeannette: a) the International Kidney Biopsy Survey (IKBS) that includes kidney biopsy diagnoses and associated patient demographics from 29 international kidney pathology laboratories, which I used to study geographic variation in glomerular disease frequencies within and across racial-ethnic groups; b) the Glomerular Disease Collaborative Network (GDCN), a registry of all kidney biopsies referred to the University of North Carolina since 1986, which I used to study temporal trends in glomerular disease frequencies within and across demographic groups over the last three decades. For the next two manuscripts (Chapters 5 and 6), I analysed data – including physician-reported cause of kidney failure – from virtually all U.S. patients with treated end-stage kidney failure who are enrolled, by federal mandate, in the United States Renal Data System (USRDS). In the first of these two manuscripts, I determined associations between glomerular disease subtype and mortality; in the second, I determined associations between glomerular disease subtype and cardiovascular events. Advanced statistical methods included multivariable regression to handle confounding, proportional sub-distribution hazard models to handle competing events, and multiple imputation to handle missing data. Results: Major findings from these manuscripts include: a) significant differences in glomerular disease frequencies across continents, even among patients with similar racial-ethnic backgrounds; b) significant temporal trends in the relative frequencies of many biopsy-proven glomerular diseases, including stabilization in the 21st century of the rapid increase in focal segmental glomerulosclerosis observed at the end of the 20th century, and a dramatic increase in diabetic glomerulosclerosis over time, to become the second most frequent biopsy-proven glomerular disease diagnosis in the modern era; c) significant differences in the hazards of mortality and cardiovascular events across glomerular disease subtypes, even after accounting for between-group differences in case-mix. Conclusions: In addition to answering specific research questions regarding glomerular disease epidemiology, this research exemplifies the strengths and feasibility of population-level, internationally collaborative, approaches to studying glomerular diseases. Findings from these studies can shape public health policy (e.g. promotion of healthy lifestyle approaches to curb the high frequency of diabetic glomerulosclerosis in contemporary U.S. populations), future research design (e.g. recognising the importance of glomerular disease subtype as a prognostic indicator in studies involving patients with end-stage kidney failure), and clinical care (e.g. formulating differential diagnoses based on patient demographics, or counselling U.S. patients regarding their absolute and relative risks of mortality and cardiovascular events following dialysis initiation)

Alternative (backdoor) androgen production and masculinization in the human fetus

Funding: The study was supported by the following grants: Chief Scientist Office (Scottish Executive, CZG/4/742) (PAF and PJOS) (http://www.cso.scot.nhs.uk/funding-2/); NHS Grampian Endowments 08/02 (PAF and PJOS) and 15/1/010 (PAF, PF, US, and PJOS) (https://www.nhsgcharities.com/); the Glasgow Children’s Hospital Research Charity Research Fund, YRSS/PHD/2016/05 (NW, MB, PJOS, and PAF) (http://www.glasgowchildrenshospitalcharity.org/research/glasgow-childrens-hospital-charity-research-fund); the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 212885 (PAF) (https://ec.europa.eu/research/fp7/index_en.cfm); Medical Research Council Grants MR/L010011/1 (PAF and PJOS) and MR/K501335/1 (MB, PAF, and PJOS) (https://mrc.ukri.org/); and the Kronprinsessan Lovisas Foundation, “Stiftelsen Gunvor och Josef Anérs,” the “Stiftelsen Jane och Dan Olssons,” and the “Stiftelsen Tornspiran” (KS and OS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Structure and agency in capabilities-enhancing homeless services: housing first, housing quality and consumer choice

The capabilities approach, a framework for understanding and measuring inequality, stipulates that equality is best understood as the freedom to do and be within a particular context. Homelessness has been referred to as a situation of ‘capabilities deprivation’, and the extent to which homeless services restore or enhance capabilities is of increasing interest. As part of a large, eight-country study of homelessness in Europe, we examined the extent to which adults with histories of homelessness perceived the services they receive as capabilities-enhancing. We collected data at two time points: baseline (nt1 = 565) and follow-up (nt2 = 399). Measures included perceived capabilities, choice and housing quality. Participants engaged with Housing First (HF) programmes perceived services as more capabilities-enhancing than participants engaged with treatment as usual (TAU); this relationship was mediated by consumer choice and perceived housing quality. Implications for social policy, practice and training are discussed

Comparison of housing first and traditional homeless service users in eight European countries: protocol for a mixed methods, multi-site study

Background: Homeless services expend considerable resources to provide for service users’ most basic needs, such as food and shelter, but their track record for ending homelessness is disappointing. An alternative model, Housing First, reversed the order of services so that homeless individuals are offered immediate access to independent housing, with wraparound supports but no treatment or abstinence requirements. Although the evidence base for Housing First’s effectiveness in ending homelessness is robust, less is known about its effectiveness in promoting recovery. Objective: The objective of this research is to compare rehabilitation- and recovery-related outcomes of homeless services users who are engaged in either Housing First or traditional staircase services in eight European countries: France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, and Sweden. Methods: A mixed methods, multi-site investigation of Housing First and traditional services will compare quantitative outcomes at two time points. Key rehabilitation outcomes include stable housing and psychiatric symptoms. Key growth outcomes include community integration and acquired capabilities. Semistructured interviews will be used to examine service users’ experiences of environmental constraints and affordances on acquired capabilities to identify features of homeless services that enhance service users’ capabilities sets. Multi-level modelling will be used to test for group differences—Housing First versus traditional services—on key outcome variables. Thematic analysis will be used to understand the ways in which service users make sense of internal and external affordances and constraints on capabilities. Results: The study is registered with the European Commission (registration number: H2020-SC6-REVINEQUAL-2016/ GA726997). Two press releases, a research report to the funding body, two peer-reviewed articles, and an e-book chapter are planned for dissemination of the final results. The project was funded from September 2016 through September 2019. Expected results will be disseminated in 2019 and 2020. Conclusions: We will use the findings from this research to formulate recommendations for European social policy on the configuration of homeless services and the scaling up and scaling out of Housing First programs. From our findings, we will draw conclusions about the setting features that promote individuals’ exits from homelessness, rehabilitation, and recovery. International Registered Report Identifier (IRRID): RR1-10.2196/1458

A large, international study on post-transplant glomerular diseases: the TANGO project

BACKGROUND: Long-term outcomes in kidney transplantation (KT) have not significantly improved during the past twenty years. Despite being a leading cause of graft failure, glomerular disease (GD) recurrence remains poorly understood, due to heterogeneity in disease pathogenesis and clinical presentation, reliance on histopathology to confirm disease recurrence, and the low incidence of individual GD subtypes. Large, international cohorts of patients with GD are urgently needed to better understand the disease pathophysiology, predictors of recurrence, and response to therapy. METHODS: The Post-TrANsplant GlOmerular Disease (TANGO) study is an observational, multicenter cohort study initiated in January 2017 that aims to: 1) characterize the natural history of GD after KT, 2) create a biorepository of saliva, blood, urine, stools and kidney tissue samples, and 3) establish a network of patients and centers to support novel therapeutic trials. The study includes 15 centers in America and Europe. Enrollment is open to patients with biopsy-proven GD prior to transplantation, including IgA nephropathy, membranous nephropathy, focal and segmental glomerulosclerosis, atypical hemolytic uremic syndrome, dense-deposit disease, C3 glomerulopathy, complement- and IgG-positive membranoproliferative glomerulonephritis or membranoproliferative glomerulonephritis type I-III (old classification). During phase 1, patient data will be collected in an online database. The biorepository (phase 2) will involve collection of samples from patients for identification of predictors of recurrence, biomarkers of disease activity or response to therapy, and novel pathogenic mechanisms. Finally, through phase 3, we will use our multicenter network of patients and centers to launch interventional studies. DISCUSSION: Most prior studies of post-transplant GD recurrence are single-center and retrospective, or rely upon registry data that frequently misclassify the cause of kidney disease. Systematically determining GD recurrence rates and predictors of clinical outcomes is essential to improving post-transplant outcomes. Furthermore, accurate molecular phenotyping and biomarker development will allow better understanding of individual GD pathogenesis, and potentially identify novel drug targets for GD in both native and transplanted kidneys. The TANGO study has the potential to tackle GD recurrence through a multicenter design and a comprehensive biorepository

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease

Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Multicenter prospective cohort study. Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years’ initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Current follow-up can only detect large differences in ESKD and death outcomes. Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes

Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study

Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases