Comparing Brief Measures of Narcissism-Internal Consistency, Validity, and Coverage.

Many measures, varying in breadth and length, have been constructed to measure narcissism. In recent years, super-short forms have become popular in research settings. Although brief measures hold some advantages, their brevity can come at psychometric costs. Participants recruited from Amazon's Mechanical Turk (N = 473) completed long and brief narcissism measures and criterion measures in a randomized order. Short forms were examined and compared to long forms in terms of their completion times and psychometric properties. Generally, the short forms demonstrated adequate internal consistency, variable convergence with each other, mostly moderate to strong convergence with long forms, and appropriate convergence with external criteria. These findings suggest that some short forms may be used when efficiency of survey administration is particularly important without significant psychometric cost. We discuss the advantages and disadvantages of the brief measures and make recommendations for which to use depending on the priorities of a given study.

Reimagining Nephrology Fellowship Education to Meet the Future Needs of Nephrology: A Report of the American Society of Nephrology Task Force on the Future of Nephrology.

The American Society of Nephrology (ASN) Task Force on the Future of Nephrology was established in April 2022 in response to requests from the American Board of Internal Medicine and the Accreditation Council for Graduate Medical Education regarding training requirements in nephrology. Given recent changes in kidney care, ASN also charged the task force with reconsidering all aspects of the specialty's future to ensure that nephrologists are prepared to provide high-quality care for people with kidney diseases. The task force engaged multiple stakeholders to develop 10 recommendations focused on strategies needed to promote: ( 1 ) just, equitable, and high-quality care for people living with kidney diseases; ( 2 ) the value of nephrology as a specialty to nephrologists, the future nephrology workforce, the health care system, the public, and government; and ( 3 ) innovation and personalization of nephrology education across the scope of medical training. This report reviews the process, rationale, and details (the "why" and the "what") of these recommendations. In the future, ASN will summarize the "how" of implementing the final report and its 10 recommendations.

Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

OBJECTIVE/BACKGROUND: Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60-70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure. METHODS: Ganciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant. RESULTS: A total of 109 consecutive patients were treated, median age 57 (range 20-73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36-104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4-42.0). One patient developed CMV disease. CONCLUSION: The use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.

Cancer-targeted photoimmunotherapy induces antitumor immunity and can be augmented by anti-PD-1 therapy for durable anticancer responses in an immunologically active murine tumor model.

The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.

Development of a Patient Preference Survey for Wearable Kidney Replacement Therapy Devices.

Background: Recent innovations have the potential to disrupt the current paradigm for kidney failure treatment. The US Food and Drug Administration is committed to incorporating valid scientific evidence about how patients weigh the benefits and risks of new devices into their decision making, but to date, premarket submission of patient preference information (PPI) has been limited for kidney devices. With input from stakeholders, we developed a survey intended to yield valid PPI, capturing how patients trade off the potential benefits and risks of wearable dialysis devices and in-center hemodialysis. Methods: We conducted concept elicitation interviews with individuals receiving dialysis to inform instrument content. After instrument drafting, we conducted two rounds of pretest interviews to evaluate survey face validity, comprehensibility, and perceived relevance. We pilot tested the survey with in-center hemodialysis patients to assess comprehensibility and usability further. Throughout, we used participant input to guide survey refinements. Results: Thirty-six individuals receiving in-center or home dialysis participated in concept elicitation (N=20) and pretest (N=16) interviews. Participants identified reduced fatigue, lower treatment burden, and enhanced freedom as important benefits of a wearable device, and many expressed concerns about risks related to device disconnection-specifically bleeding and infection. We drafted a survey that included descriptions of the risks of serious bleeding and serious infection and an assessment of respondent willingness to wait for a safer device. Input from pretest interviewees led to various instrument modifications, including treatment descriptions, item wording, and risk-level explanations. Pilot testing of the updated survey among 24 in-center hemodialysis patients demonstrated acceptable survey comprehensibility and usability, although 50% of patients required some assistance. Conclusions: The final survey is a 54-item web-based instrument that will yield estimates of the maximal acceptable risk for the described wearable device and willingness to wait for wearable devices with lower risk.

Kidney Health Initiative ESKD Data Standards Project.

The end-stage kidney disease (ESKD) Data Standards Project was launched by the Kidney Health Initiative (KHI) with the goal of standardizing dialysis-related measurements for research use. KHI is a public-private partnership between the American Society of Nephrology, US Food and Drug Administration, and organizations with an interest in kidney disease. KHI promotes safe and effective patient-centered therapies for people with kidney disease. In 2018, KHI established a workgroup with expertise in nephrology, nursing, quality management, ESKD data, organizational management, and clinical research. The workgroup identified 5 topic areas and 8 specific measures for the development of standards on the basis of the existing ESKD Measurement Specification Manual published by the Centers for Medicare & Medicaid Services. The topic areas were ultrafiltration rate, vascular access, dialysis small solute clearance (3 data standards), hospitalization (2 data standards), and mortality. The research standards were approved by the workgroup, reviewed by external reviewers, and opened to public comment. The data standards attempt to achieve balance between brevity and completeness in the face of knowledge gaps. The ESKD Data Standards are publicly available on the KHI website (https://khi.asn-online.org/projects/project.aspx?ID=78).

Conceptual Framework for Patient-Reported Outcome Measures in Clinical Trials of Skeletal Muscle Cramping Experienced in Dialysis: A Kidney Health Initiative Workgroup Report.

Skeletal muscle cramping is a common and bothersome symptom for patients on maintenance dialysis therapy, regardless of modality, and it has not been prioritized for innovative assessments or treatments. Research to prevent or treat skeletal muscle cramping in patients receiving dialysis is hindered by poorly understood pathophysiology, lack of an accepted definition, and the absence of a standardized measurement method. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a multidisciplinary workgroup to define a set of patient-reported outcome measures for use in clinical trials to test the effect of new dialysis devices, new KRTs, lifestyle/behavioral modifications, and medications on skeletal muscle cramping. Upon determining that foundational work was necessary, the workgroup undertook a multistep process to elicit concepts central to developing the basis for demonstrating content validity of candidate patient-reported outcome measures for skeletal muscle cramping in patients on dialysis. The workgroup sought to (1) create an accepted, patient-endorsed definition for skeletal muscle cramping that applies to all dialysis modalities, (2) construct a conceptual model for developing and evaluating a skeletal muscle cramping-specific patient-reported outcome measure, and (3) identify potential questions from existing patient-reported outcome measures that could be modified or adapted and subsequently tested in the dialysis population. We report the results of the workgroup's efforts, provide our recommendations, and issue a call to action to address the gaps in knowledge and research needs we identified. These action steps are urgently needed to quantify skeletal muscle cramping burden, assess the effect, and measure meaningful changes of new interventions to improve the experience of patients receiving dialysis and suffering from skeletal muscle cramping.

Understanding and Overcoming the Challenges Related to Cardiovascular Trials Involving Patients with Kidney Disease.

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.

The Community Health Systems Reform Cycle: Strengthening the Integration of Community Health Worker Programs Through an Institutional Reform Perspective.

To develop guidance for governments and partners seeking to scale community health worker programs, we developed a conceptual framework, collected observations from the scale-up efforts of 7 countries, workshopped the framework with technical groups and with country stakeholders, and reviewed literature in the areas of health and policy reform, change management, institutional development, health systems, and advocacy. We observed that successful scale-up is a complex process of institutional reform. Successful scale-up: (1) depends on a carefully choreographed, problem-driven political process; (2) requires that scaled program models are drawn from solutions that are available in a given health system context and aligned with the resources, capabilities, and commitments of key health sector stakeholders; and (3) emerges from iterative cycles of learning and improvement, rather than a single, linear scale-up effort. We identify stages of the reform process associated with each of these 3 findings: problem prioritization, coalition building, solution gathering, design, program readiness, launch, governance, and management and learning. The resulting Community Health Systems Reform Cycle can be used by government, donors, and nongovernmental partners to prioritize and design community health worker scale-up efforts, diagnose challenges or gaps in successful scale-up and integration, and coordinate the contributions of diverse stakeholders.

Pathophysiology and Treatment of Enteric Hyperoxaluria.

Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.

CD8+ T cells mediate protection against Zika virus induced by an NS3-based vaccine.

Zika virus (ZIKV) is associated with congenital malformations in infants born to infected mothers, and with Guillain-Barré syndrome in infected adults. Development of ZIKV vaccines has focused predominantly on the induction of neutralizing antibodies, although a suboptimal antibody response may theoretically enhance disease severity through antibody-dependent enhancement (ADE). Here, we report induction of a protective anti-ZIKV CD8+ T cell response in the HLA-B*0702 Ifnar1-/- transgenic mice using an alphavirus-based replicon RNA vaccine expressing ZIKV nonstructural protein NS3, a potent T cell antigen. The NS3 vaccine did not induce a neutralizing antibody response but elicited polyfunctional CD8+ T cells that were necessary and sufficient for preventing death in lethally infected adult mice and fetal growth restriction in infected pregnant mice. These data identify CD8+ T cells as the major mediators of ZIKV NS3 vaccine-induced protection and suggest a new strategy to develop safe and effective anti-flavivirus vaccines.

Toward Patient-Centered Innovation: A Conceptual Framework for Patient-Reported Outcome Measures for Transformative Kidney Replacement Devices.

Individuals with dialysis-dependent kidney failure experience considerable disease- and treatment-related decline in functional status and overall well-being. Despite these experiences, there have been few substantive technological advances in KRT in decades. As such, new federal initiatives seek to accelerate innovation. Historically, integration of patient perspectives into KRT product development has been limited. However, the US Food and Drug Administration recognizes the importance of incorporating patient perspectives into the total product life cycle (i.e., from product conception to postmarket surveillance) and encourages the consideration of patient-reported outcomes in regulatory-focused clinical trials when appropriate. Recognizing the significance of identifying patient-reported outcome measures (PROMs) that capture contemporary patient priorities, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to (1) develop a conceptual framework for a health-related quality of life PROM; (2) identify and map existing PROMs to the conceptual framework, prioritizing them on the basis of their supporting evidence for use in the regulatory environment; and (3) describe next steps for identifying PROMs for use in regulatory clinical trials of transformative KRT devices. This paper summarizes the proposed health-related quality-of-life PROM conceptual framework, maps and prioritizes PROMs, and identifies gaps and future needs to advance the development of rigorous, meaningful PROMS for use in clinical trials of transformative KRT devices.

End Points for Clinical Trials in Primary Hyperoxaluria.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

A Technology Roadmap for Innovative Approaches to Kidney Replacement Therapies: A Catalyst for Change.

The number of patients dialyzed for ESKD exceeds 500,000 in the United States and more than 2.6 million people worldwide, with the expectation that the worldwide number will double by 2030. The human cost of health and societal financial cost of ESKD is substantial. Dialytic therapy is associated with an unacceptably high morbidity and mortality rate and poor quality of life. Although innovation in many areas of science has been transformative, there has been little innovation in dialysis or alternatives for kidney replacement therapy (KRT) since its introduction approximately 70 years ago. Advances in kidney biology, stem cells and kidney cell differentiation protocols, biomaterials, sensors, nano/microtechnology, sorbents and engineering, and interdisciplinary approaches and collaborations can lead to disruptive innovation. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, has convened a multidisciplinary group to create a technology roadmap for innovative approaches to KRT to address patients' needs. The Roadmap is a living document. It identifies the design criteria that must be considered to replace the myriad functions of the kidney, as well as scientific, technical, regulatory, and payor milestones required to commercialize and provide patient access to KRT alternatives. Various embodiments of potential solutions are discussed, but the Roadmap is agnostic to any particular solution set. System enablers are identified, including vascular access, biomaterial development, biologic and immunologic modulation, function, and safety monitoring. Important Roadmap supporting activities include regulatory alignment and innovative financial incentives and payment pathways. The Roadmap provides estimated timelines for replacement of specific kidney functions so that approaches can be conceptualized in ways that are actionable and attract talented innovators from multiple disciplines. The Roadmap has been used to guide the selection of KidneyX prizes for innovation in KRT.

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

OBJECTIVE: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.