Integrating socio-economic vulnerability factors improves neighborhood-scale wastewater-based epidemiology for public health applications.

Wastewater Based Epidemiology (WBE) of COVID-19 is a low-cost, non-invasive, and inclusive early warning tool for disease spread. Previously studied WBE focused on sampling at wastewater treatment plant scale, limiting the level at which demographic and geographic variations in disease dynamics can be incorporated into the analysis of certain neighborhoods. This study demonstrates the integration of demographic mapping to improve the WBE of COVID-19 and associated post-COVID disease prediction (here kidney disease) at the neighborhood level using machine learning. WBE was conducted at six neighborhoods in Seattle during October 2020 - February 2022. Wastewater processing and RT-qPCR were performed to obtain SARS-CoV-2 RNA concentration. Census data, clinical data of COVID-19, as well as patient data of acute kidney injury (AKI) cases reported during the study period were collected and the distribution across the city was studied using Geographic Information System (GIS) mapping. Further, we analyzed the data set to better understand socioeconomic impacts on disease prevalence of COVID-19 and AKI per neighborhood. The heterogeneity of eleven demographic factors (such as education and age among others) was observed within neighborhoods across the city of Seattle. Dynamics of COVID-19 clinical cases and wastewater SARS-CoV-2 varied across neighborhood with different levels of demographics. Machine learning models trained with data from the earlier stages of the pandemic were able to predict both COVID-19 and AKI incidence in the later stages of the pandemic (Spearman correlation coefficient of 0·546 - 0·904), with the most predictive model trained on the combination of wastewater data and demographics. The integration of demographics strengthened machine learning models' capabilities to predict prevalence of COVID-19, and of AKI as a marker for post-COVID sequelae. Demographic-based WBE presents an effective tool to monitor and manage public health beyond COVID-19 at the neighborhood level.

Kidney microphysiological models for nephrotoxicity assessment.

Nephrotoxicity testing is an important step in preclinical development of new molecular entities (NMEs) and has traditionally been performed in 2-D cell culture systems and animal models. However, 2-D culture systems fail to replicate complex in vivo microenvironment and animal models face interspecies differences including the overexpression of drug transporters. In the last decade, 3-D microphysiological systems (MPS) have been developed to address these concerns. Here, we review recent advancements in kidney MPS and their application in drug-induced toxicity testing and kidney disease research. We find that current research is making significant progress addressing MPS limitations such as throughput, incorporating various regions of the nephron such as the glomerulus, and successfully modeling and predicting clinically relevant nephrotoxicity of current and new drugs.

Precision-porous polyurethane elastomers engineered for application in pro-healing vascular grafts: Synthesis, fabrication and detailed biocompatibility assessment.

Unmet needs for small diameter, non-biologic vascular grafts and the less-than-ideal performance of medium diameter grafts suggest opportunities for major improvements. Biomaterials that are mechanically matched to native blood vessels, reduce the foreign body capsule (FBC) and demonstrate improved integration and healing are expected to improve graft performance. In this study, we developed biostable, crosslinked polyurethane formulations and used them to fabricate scaffolds with precision-engineered 40 µm pores. We matched the scaffold mechanical properties with those of native blood vessels by optimizing the polyurethane compositions. We hypothesized that such scaffolds promote healing and mitigate the FBC. To test our hypothesis, polyurethanes with 40 µm pores, 100 µm pores, and non-porous slabs were implanted subcutaneously in mice for 3 weeks, and then were examined histologically. Our results show that 40 µm porous scaffolds elicit the highest level of angiogenesis, cellularization, and the least severe foreign body capsule (based on a refined assessment method). This study presents the first biomaterial with tuned mechanical properties and a precision engineered porous structure optimized for healing, thus can be ideal for pro-healing vascular grafts and in situ vascular engineering. In addition, these scaffolds may have wide applications in tissue engineering, drug delivery, and implantable device.

Assessment of kidney proximal tubular secretion in critical illness.

BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were lower in critically ill patients compared with healthy individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each SD higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% to 38% lower) independent of severity of illness, SCr, and tubular injury markers. Higher urine-to-plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing.CONCLUSIONAmong critically ill adults, tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential ICU medications.FUNDINGGrants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH) K23DK116967, the University of Washington Diabetes Research Center P30DK017047, an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers, and the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Integrating Patient Priorities with Science by Community Engagement in the Kidney Precision Medicine Project.

The Kidney Precision Medicine Project (KPMP) is a multisite study designed to improve understanding of CKD attributed to diabetes or hypertension and AKI by performing protocol-driven kidney biopsies. Study participants and their kidney tissue samples undergo state-of-the-art deep phenotyping using advanced molecular, imaging, and data analytical methods. Few patients participate in research design or concepts for discovery science. A major goal of the KPMP is to include patients as equal partners to inform the research for clinically relevant benefit. The purpose of this report is to describe patient and community engagement and the value they bring to the KPMP. Patients with CKD and AKI and clinicians from the study sites are members of the Community Engagement Committee, with representation on other KPMP committees. They participate in KPMP deliberations to address scientific, clinical, logistic, analytic, ethical, and community engagement issues. The Community Engagement Committee guides KPMP research priorities from perspectives of patients and clinicians. Patients led development of essential study components, including the informed consent process, no-fault harm insurance coverage, the ethics statement, return of results plan, a "Patient Primer" for scientists and the public, and Community Advisory Boards. As members across other KPMP committees, the Community Engagement Committee assures that the science is developed and conducted in a manner relevant to study participants and the clinical community. Patients have guided the KPMP to produce research aligned with their priorities. The Community Engagement Committee partnership has set new benchmarks for patient leadership in precision medicine research.

The current and future landscape of dialysis.

The development of dialysis by early pioneers such as Willem Kolff and Belding Scribner set in motion several dramatic changes in the epidemiology, economics and ethical frameworks for the treatment of kidney failure. However, despite a rapid expansion in the provision of dialysis - particularly haemodialysis and most notably in high-income countries (HICs) - the rate of true patient-centred innovation has slowed. Current trends are particularly concerning from a global perspective: current costs are not sustainable, even for HICs, and globally, most people who develop kidney failure forego treatment, resulting in millions of deaths every year. Thus, there is an urgent need to develop new approaches and dialysis modalities that are cost-effective, accessible and offer improved patient outcomes. Nephrology researchers are increasingly engaging with patients to determine their priorities for meaningful outcomes that should be used to measure progress. The overarching message from this engagement is that while patients value longevity, reducing symptom burden and achieving maximal functional and social rehabilitation are prioritized more highly. In response, patients, payors, regulators and health-care systems are increasingly demanding improved value, which can only come about through true patient-centred innovation that supports high-quality, high-value care. Substantial efforts are now underway to support requisite transformative changes. These efforts need to be catalysed, promoted and fostered through international collaboration and harmonization.

Health Policy for Dialysis Care in Canada and the United States.

Contemporary dialysis treatment for chronic kidney failure is complex, is associated with poor clinical outcomes, and leads to high health costs, all of which pose substantial policy challenges. Despite similar policy goals and universal access for their kidney failure programs, the United States and Canada have taken very different approaches to dealing with these challenges. While US dialysis care is primarily government funded and delivered predominantly by private for-profit providers, Canadian dialysis care is also government funded but delivered almost exclusively in public facilities. Differences also exist for regulatory mechanisms and the policy incentives that may influence the behavior of providers and facilities. These differences in health policy are associated with significant variation in clinical outcomes: mortality among patients on dialysis is consistently lower in Canada than in the United States, although the gap has narrowed in recent years. The observed heterogeneity in policy and outcomes offers important potential opportunities for each health system to learn from the other. This article compares and contrasts transnational dialysis-related health policies, focusing on key levers including payment, finance, regulation, and organization. We also describe how policy levers can incentivize favorable practice patterns to support high-quality/high-value, person-centered care and to catalyze the emergence of transformative technologies for alternative kidney replacement strategies.

Translational Assessment of Drug-Induced Proximal Tubule Injury Using a Kidney Microphysiological System.

Drug-induced kidney injury, a major cause of acute kidney injury, results in progressive kidney disease and is linked to increased mortality in hospitalized patients. Primary injury sites of drug-induced kidney injury are proximal tubules. Clinically, kidney injury molecule-1, an established tubule-specific biomarker, is monitored to assess the presence and progression of injury. The ability to accurately predict drug-related nephrotoxicity preclinically would reduce patient burden and drug attrition rates, yet state-of-the-art in vitro and animal models fail to do so. In this study, we demonstrate the use of kidney injury molecule-1 measurement in the kidney microphysiological system as a preclinical model for drug toxicity assessment. To show clinical relevance, we use quantitative systems pharmacology computational models for in vitro-in vivo translation of the experimental results and to identify favorable dosing regimens for one of the tested drugs.

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.

Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs on chips" - are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10-16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)-like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.

Comparison of the Complexity of Patients Seen by Different Medical Subspecialists in a Universal Health Care System.

Importance: Clinical experience suggests that there are substantial differences in patient complexity across medical specialties, but empirical data are lacking. Objective: To compare the complexity of patients seen by different types of physician in a universal health care system. Design, Setting, and Participants: Population-based retrospective cohort study of 2 597 127 residents of the Canadian province of Alberta aged 18 years and older with at least 1 physician visit between April 1, 2014 and March 31, 2015. Data were analyzed in September 2018. Exposures: Type of physician seeing each patient (family physician, general internist, or 11 types of medical subspecialist) assessed as non-mutually exclusive categories. Main Outcomes and Measures: Nine markers of patient complexity (number of comorbidities, presence of mental illness, number of types of physicians involved in each patient's care, number of physicians involved in each patient's care, number of prescribed medications, number of emergency department visits, rate of death, rate of hospitalization, rate of placement in a long-term care facility). Results: Among the 2 597 127 participants, the median (interquartile range) age was 46 (32-59) years and 54.1% were female. Over 1 year of follow-up, 21 792 patients (0.8%) died, the median (range) number of days spent in the hospital was 0 (0-365), 8.1% of patients had at least 1 hospitalization, and the median (interquartile range) number of prescribed medications was 3 (1-7). When the complexity markers were considered individually, patients seen by nephrologists had the highest mean number of comorbidities (4.2; 95% CI, 4.2-4.3 vs [lowest] 1.1; 95% CI, 1.0-1.1), highest mean number of prescribed medications (14.2; 95% CI, 14.2-14.3 vs [lowest] 4.9; 95% CI, 4.9-4.9), highest rate of death (6.6%; 95% CI, 6.3%-6.9% vs [lowest] 0.1%; 95% CI, <0.1%-0.2%), and highest rate of placement in a long-term care facility (2.0%; 95% CI, 1.8%-2.2% vs [lowest] <0.1%; 95% CI, <0.1%-0.1%). Patients seen by infectious disease specialists had the highest complexity as assessed by the other 5 markers: rate of a mental health condition (29%; 95% CI, 28%-29% vs [lowest] 14%; 95% CI, 14%-14%), mean number of physician types (5.5; 95% CI, 5.5-5.6 vs [lowest] 2.1; 95% CI, 2.1-2.1), mean number of physicians (13.0; 95% CI, 12.9-13.1 vs [lowest] 3.8; 95% CI, 3.8-3.8), mean days in hospital (15.0; 95% CI, 14.9-15.0 vs [lowest] 0.4; 95% CI, 0.4-0.4), and mean emergency department visits (2.6; 95% CI, 2.6-2.6 vs [lowest] 0.5; 95% CI, 0.5-0.5). When types of physician were ranked according to patient complexity across all 9 markers, the order from most to least complex was nephrologist, infectious disease specialist, neurologist, respirologist, hematologist, rheumatologist, gastroenterologist, cardiologist, general internist, endocrinologist, allergist/immunologist, dermatologist, and family physician. Conclusion and Relevance: Substantial differences were found in 9 different markers of patient complexity across different types of physician, including medical subspecialists, general internists, and family physicians. These findings have implications for medical education and health policy.

Risk prediction to inform surveillance of chronic kidney disease in the US Healthcare Safety Net: a cohort study.

BACKGROUND: The capacity of electronic health record (EHR) data to guide targeted surveillance in chronic kidney disease (CKD) is unclear. We sought to leverage EHR data for predicting risk of progressing from CKD to end-stage renal disease (ESRD) to help inform surveillance of CKD among vulnerable patients from the healthcare safety-net. METHODS: We conducted a retrospective cohort study of adults (n = 28,779) with CKD who received care within 2 regional safety-net health systems during 1996-2009 in the Western United States. The primary outcomes were progression to ESRD and death as ascertained by linkage with United States Renal Data System and Social Security Administration Death Master files, respectively, through September 29, 2011. We evaluated the performance of 3 models which included demographic, comorbidity and laboratory data to predict progression of CKD to ESRD in conditions commonly targeted for disease management (hypertension, diabetes, chronic viral diseases and severe CKD) using traditional discriminatory criteria (AUC) and recent criteria intended to guide population health management strategies. RESULTS: Overall, 1730 persons progressed to end-stage renal disease and 7628 died during median follow-up of 6.6 years. Performance of risk models incorporating common EHR variables was highest in hypertension, intermediate in diabetes and chronic viral diseases, and lowest in severe CKD. Surveillance of persons who were in the highest quintile of ESRD risk yielded 83-94 %, 74-95 %, and 75-82 % of cases who progressed to ESRD among patients with hypertension, diabetes and chronic viral diseases, respectively. Similar surveillance yielded 42-71 % of ESRD cases among those with severe CKD. Discrimination in all conditions was universally high (AUC ≥0.80) when evaluated using traditional criteria. CONCLUSIONS: Recently proposed discriminatory criteria account for varying risk distribution and when applied to common clinical conditions may help to inform surveillance of CKD in diverse populations.

Cost-effectiveness of antiplatelet therapy to prolong primary patency of hemodialysis graft.

INTRODUCTION: The Dialysis Access Consortium (DAC) study group previously reported that treatment with extended-release dipyridamole plus aspirin (DASA) resulted in a significant but clinically modest improvement in primary unassisted arteriovenous graft (AVG) patency. Utilizing DAC published data, the objective of this study is to evaluate the cost effectiveness of antiplatelet interventions aimed at preventing loss of primary AVG patency in hemodialysis (HD) patients. METHODS: We performed a cost-utility analysis, using a decision analysis tree model with a 12-month time horizon and a third party payer perspective. Interventions included DASA with and without concurrent aspirin, aspirin alone, and no prophylaxis. The modeled population was defined as adult (≥ 18 years of age) end-stage renal disease (ESRD) patients who had undergone placement of a new AVG in the United States. The outcomes were costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios, and net monetary benefit. Probabilities were based upon published studies performed by the DAC Study Group while costs of medications and procedures were drawn from public sources. Utilities of health states were derived from published reports and the Short Form 6D (SF-6D) instrument. RESULTS: Aspirin alone is the most cost effective strategy for AVG pharmacologic prophylaxis, as compared to no prophylaxis or DASA with or without concurrent aspirin. The results are robust on multiple scenario analyses using both deterministic and Monte Carlo probabilistic sensitivity analyses. Accounting for both costs and QALY, using aspirin alone to prevent AVG thrombosis can potentially reduce healthcare costs by $24,679,412 per year compared to no aspirin use, at a willingness-to-pay of $50,000/ QALY. CONCLUSIONS: Aspirin monotherapy compared favorably to other strategies based on cost per QALY. Our findings support the use of aspirin prophylaxis in HD patients with a new AVG who do not have a contraindication to aspirin.

Assessment of physical activity in chronic kidney disease.

BACKGROUND: Physical inactivity plays an important role in the development of kidney disease and its complications; however, the validity of standard tools for measuring physical activity (PA) is not well understood. STUDY DESIGN: We investigated the performance of several readily available and widely used PA and physical function questionnaires, individually and in combination, against accelerometry among a cohort of chronic kidney disease (CKD) participants. SETTING AND PARTICIPANTS: Forty-six participants from the Seattle Kidney Study, an observational cohort study of persons with CKD, completed the Physical Activity Scale for the Elderly, Human Activity Profile (HAP), Medical Outcomes Study SF-36 questionnaire, and the Four-week Physical Activity History questionnaires. We simultaneously measured PA using an Actigraph GT3X accelerometer during a 14-day period. We estimated the validity of each instrument by testing its associations with log-transformed accelerometry counts. We used the Akaike information criterion to investigate the performance of combinations of questionnaires. RESULTS: All questionnaire scores were significantly associated with log-transformed accelerometry counts. The HAP correlated best with accelerometry counts (r(2) = 0.32) followed by SF-36 (r(2) = 0.23). Forty-three percent of the variability in accelerometry counts data was explained by a model that combined the HAP, SF-36, and Four-week Physical Activity History questionnaires. CONCLUSION: A combination of measurement tools can account for a modest component of PA in patients with CKD; however, a substantial proportion of PA is not captured by standard assessments.

Regional differences in dialysis care and mortality among American Indians and Alaska Natives.

American Indians/Alaska Natives (AIANs) compose a heterogeneous population that includes geographically distinct tribal communities, many with high rates of ESRD. Regional features of dialysis care and mortality are unknown in this population. Here, we describe the structure of dialysis care and mortality of adult AIANs who initiated maintenance dialysis during 1995-2008 in different regions of the US. Overall, 13,716 AIANs received dialysis at 2054 facilities. Approximately 10% (n = 197) of these facilities provided care to two-thirds (n = 9011) of AIANs. AIANs from the Southwest and Alaska were concentrated in relatively few dialysis facilities whereas those in the Eastern US and Pacific Coast were distributed more diffusely. Despite comparably high rates of poverty, diabetes, and cardiovascular disease, annual mortality rates were lower in the Southwest (13.9%) compared with the Southern Plains (23.2%), Alaska (21.2%), Eastern US (20.0%), Northern Plains (20.8%), and Pacific Coast (22.0%). These regional differences were consistent over time and persisted after adjusting for sociodemographic and clinical variables and area-based poverty. In conclusion, regional differences in the structure of dialysis care and patient mortality exist among AIANs. Southwestern AIANs experience the highest concentration of dialysis care and the lowest mortality. Our findings suggest that an area-based approach examining the care structure of relatively few dialysis facilities may delineate determinants of these differences and improve the quality of care to many AIAN communities.

Continuous renal replacement therapy in the treatment of acute renal failure: critical assessment is required.

A continuous approach to renal replacement therapy (CRRT) for critically ill patients was introduced in 1977 and was hailed almost immediately as an improved alternative to intermittent hemodialysis (IHD). Now that CRRT has been in clinical practice for three decades, it is fair to ask whether research-based evidence (rather than expert opinion) supports the use of this complex technology in comparison to IHD. Several randomized clinical trials have compared the outcomes of CRRT and IHD. In one trial, patients assigned to CRRT had a significantly higher intensive-care mortality rate. In other recent trials, there has been no significant difference in outcome. A meta-analysis of observational studies similarly shows no benefit of CRRT versus IHD, with recent trends actually favoring IHD. While considerable attention has been focused on perceived benefits of CRRT compared to IHD, comparatively less attention has been focused on the potential for increased risks. When examining the totality of evidence from recent observational studies and clinical trials, there is no convincing evidence to support superiority of CRRT over IHD in the treatment of critically ill patients with ARF.