NSAID-associated acute kidney injury in hospitalized children - a prospective Pediatric Nephrology Research Consortium study.

BACKGROUND: Acute kidney injury (AKI) in children has serious short-term and long-term consequences. We sought 1) to prospectively describe NSAID-associated AKI in hospitalized children; 2) to determine if NSAID-associated AKI was more severe in younger children < 5 years; and 3) to follow outcomes after hospitalization for NSAID-associated AKI. METHODS: This was a prospective, multi-center study in hospitalized children 1 month to 18 years. Parents/guardians were given a brief questionnaire to determine the dosing, duration, and type of NSAIDs given. Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria were used to stage AKI severity. Patients with other causes of AKI were excluded (e.g., other nephrotoxins, sepsis, malignancy, etc.). RESULTS: We identified 25 patients with NSAID-associated AKI, accounting for 3.1% of AKI. All 25 had AKI upon hospital presentation. The median age was 15.5 years, and 20/25 (80%) had volume depletion. Median duration of NSAID use was 2 days, and 63% of patients took the normal recommended NSAID dose. Median hospital length of stay was 4 days, and none required dialysis. At the most recent estimated glomerular filtration rate (eGFR) after discharge (available in 17/25 patients), only 4/17 (24%) had eGFR ≥ 90 ml/min/1.73 m2, and 13/17 (76%) had eGFR 60 to < 90 ml/min/1.73 m2, indicative of abnormal kidney function. CONCLUSIONS: NSAID-associated AKI usually occurs with recommended NSAID dosing in the setting of dehydration. Follow-up after AKI showed a substantial rate of CKD. Therefore, we recommend that NSAIDs should not be used in dehydrated children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Developing an AKI Consensus Definition for Database Research: Findings From a Scoping Review and Expert Opinion Using a Delphi Process.

RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) definition of acute kidney injury (AKI) is frequently used in studies to examine the epidemiology of AKI. This definition is variably interpreted and applied to routinely collected health care data. The aim of this study was to examine this variation and to achieve consensus in how AKI should be defined for research using routinely collected health care data. SOURCES OF EVIDENCE AND STUDY DESIGN: Scoping review via searching Medline and EMBASE for studies using health care data to examine AKI by using the KDIGO creatinine-based definition. An international panel of experts formed to participate in a modified Delphi process to attempt to generate consensus about how AKI should be defined when using routinely collected laboratory data. CHARTING METHODS AND ANALYTICAL APPROACH: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension for scoping reviews was followed. For the Delphi process, 2 rounds of questions were distributed via internet-based questionnaires to all participants with a prespecified cutoff of 75% agreement used to define consensus. RESULTS: The scoping review found 174 studies that met the inclusion criteria. The KDIGO definition was inconsistently applied, and the methods for application were poorly described. We found 58 (33%) of papers did not provide a definition of how the baseline creatinine value was determined, and only 34 (20%) defined recovery of kidney function. Of 55 invitees to the Delphi process, 35 respondents participated in round 1, and 25 participated in round 2. Some consensus was achieved in areas related to how to define the baseline creatinine value, which patients should be excluded from analysis of routinely collected laboratory data, and how persistent chronic kidney disease or nonrecovery of AKI should be defined. LIMITATIONS: The Delphi panel members predominantly came from the United Kingdom, the United States, and Canada, and there were low response rates for some questions in round 1. CONCLUSIONS: The current methods for defining AKI using routinely collected data are inconsistent and poorly described in the available literature. Experts could not achieve consensus for many aspects of defining AKI and describing its sequelae. The KDIGO guidelines should be extended to include a standardized definition for how AKI should be defined when using routinely collected data.

Establishing a Core Outcome Set for Peritoneal Dialysis: Report of the SONG-PD (Standardized Outcomes in Nephrology-Peritoneal Dialysis) Consensus Workshop.

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD.

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.

Ethical Issues in Pragmatic Cluster-Randomized Trials in Dialysis Facilities.

A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution.

How Omics Data Can Be Used in Nephrology.

Advances in technology and computing now permit the high-throughput analysis of multiple domains of biological information, including the genome, transcriptome, proteome, and metabolome. These omics approaches, particularly comprehensive analysis of the genome, have catalyzed major discoveries in science and medicine, including in nephrology. However, they also generate large complex data sets that can be difficult to synthesize from a clinical perspective. This article seeks to provide an overview that makes omics technologies relevant to the practicing nephrologist, framing these tools as an extension of how we approach patient care in the clinic. More specifically, omics technologies reinforce the impact that genetic mutations can have on a range of kidney disorders, expand the catalogue of uremic molecules that accumulate in blood with kidney failure, enhance our ability to scrutinize urine beyond urinalysis for insight on renal pathology, and enable more extensive characterization of kidney tissue when a biopsy is performed. Although assay methodologies vary widely, all omics technologies share a common conceptual framework that embraces unbiased discovery at the molecular level. Ultimately, the application of these technologies seeks to elucidate a more mechanistic and individualized approach to the diagnosis and treatment of human disease.

Report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop on Establishing a Core Outcome Measure for Hemodialysis Vascular Access.

Vascular access outcomes in hemodialysis are critically important for patients and clinicians, but frequently are neither patient relevant nor measured consistently in randomized trials. A Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) consensus workshop was convened to discuss the development of a core outcome measure for vascular access. 13 patients/caregivers and 46 professionals (clinicians, policy makers, industry representatives, and researchers) attended. Participants advocated for vascular access function to be a core outcome based on the broad applicability of function regardless of access type, involvement of a multidisciplinary team in achieving a functioning access, and the impact of access function on quality of life, survival, and other access-related outcomes. A core outcome measure for vascular access required demonstrable feasibility for implementation across different clinical and trial settings. Participants advocated for a practical and flexible outcome measure with a simple actionable definition. Integrating patients' values and preferences was warranted to enhance the relevance of the measure. Proposed outcome measures for function included "uninterrupted use of the access without the need for interventions" and "ability to receive prescribed dialysis," but not "access blood flow," which was deemed too expensive and unreliable. These recommendations will inform the definition and implementation of a core outcome measure for vascular access function in hemodialysis trials.

Perspectives on Research Participation and Facilitation Among Dialysis Patients, Clinic Personnel, and Medical Providers: A Focus Group Study.

BACKGROUND: Most prospective studies involving individuals receiving maintenance dialysis have been small, and many have had poor clinical translatability. Research relevance can be enhanced through stakeholder engagement. However, little is known about dialysis clinic stakeholders' perceptions of research participation and facilitation. The objective of this study was to characterize the perspectives of dialysis clinic stakeholders (patients, clinic personnel, and medical providers) on: (1) research participation by patients and (2) research facilitation by clinic personnel and medical providers. We also sought to elucidate stakeholder preferences for research communication. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: 7 focus groups (59 participants: 8 clinic managers, 14 nurses/patient care technicians, 8 social workers/dietitians, 11 nephrologists/advanced practice providers, and 18 patients/care partners) from 7 North Carolina dialysis clinics. METHODOLOGY: Clinics and participants were purposively sampled. Focus groups were recorded and transcribed. ANALYTICAL APPROACH: Thematic analysis. RESULTS: We identified 11 themes that captured barriers to and facilitators of research participation by patients and research facilitation by clinic personnel and medical providers. We collapsed these themes into 4 categories to create an organizational framework for considering stakeholder (narrow research understanding, competing personal priorities, and low patient literacy and education levels), relationship (trust, buy-in, and altruistic motivations), research design (convenience, follow-up, and patient incentives), and dialysis clinic (professional demands, teamwork, and communication) aspects that may affect stakeholder interest in participating in or facilitating research. These themes appear to shape the degree of research readiness of a dialysis clinic environment. Participants preferred short research communications delivered in multiple formats. LIMITATIONS: Potential selection bias and inclusion of English-speaking participants only. CONCLUSIONS: Our findings revealed patient interest in participating in research and clinical personnel and medical provider interest in facilitating research. Overall, our results suggest that dialysis clinic research readiness may be enhanced through increased stakeholder research knowledge and alignment of clinical and research activities.

Establishing a Core Outcome Measure for Fatigue in Patients on Hemodialysis: A Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop Report.

Fatigue is one of the most highly prioritized outcomes for patients and clinicians, but remains infrequently and inconsistently reported across trials in hemodialysis. We convened an international Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) consensus workshop with stakeholders to discuss the development and implementation of a core outcome measure for fatigue. 15 patients/caregivers and 42 health professionals (clinicians, researchers, policy makers, and industry representatives) from 9 countries participated in breakout discussions. Transcripts were analyzed thematically. 4 themes for a core outcome measure emerged. Drawing attention to a distinct and all-encompassing symptom was explicitly recognizing fatigue as a multifaceted symptom unique to hemodialysis. Emphasizing the pervasive impact of fatigue on life participation justified the focus on how fatigue severely impaired the patient's ability to do usual activities. Ensuring relevance and accuracy in measuring fatigue would facilitate shared decision making about treatment. Minimizing burden of administration meant avoiding the cognitive burden, additional time, and resources required to use the measure. A core outcome measure that is simple, is short, and includes a focus on the severity of the impact of fatigue on life participation may facilitate consistent and meaningful measurement of fatigue in all trials to inform decision making and care of patients receiving hemodialysis.

Establishing Core Outcome Domains in Hemodialysis: Report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop.

Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider evolving priorities over time, deconstruction of language and meaning for conceptual consistency and clarity, understanding of potential overlap and associations between outcomes, and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive, and validated outcome measures that could be used in clinical care (quality indicators) and trials (including pragmatic trials) and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment and improved patient outcomes.

Ethical Dilemmas in Using AI for Academic Writing and an Example Framework for Peer Review in Nephrology Academia: A Narrative Review.

The emergence of artificial intelligence (AI) has greatly propelled progress across various sectors including the field of nephrology academia. However, this advancement has also given rise to ethical challenges, notably in scholarly writing. AI's capacity to automate labor-intensive tasks like literature reviews and data analysis has created opportunities for unethical practices, with scholars incorporating AI-generated text into their manuscripts, potentially undermining academic integrity. This situation gives rise to a range of ethical dilemmas that not only question the authenticity of contemporary academic endeavors but also challenge the credibility of the peer-review process and the integrity of editorial oversight. Instances of this misconduct are highlighted, spanning from lesser-known journals to reputable ones, and even infiltrating graduate theses and grant applications. This subtle AI intrusion hints at a systemic vulnerability within the academic publishing domain, exacerbated by the publish-or-perish mentality. The solutions aimed at mitigating the unethical employment of AI in academia include the adoption of sophisticated AI-driven plagiarism detection systems, a robust augmentation of the peer-review process with an "AI scrutiny" phase, comprehensive training for academics on ethical AI usage, and the promotion of a culture of transparency that acknowledges AI's role in research. This review underscores the pressing need for collaborative efforts among academic nephrology institutions to foster an environment of ethical AI application, thus preserving the esteemed academic integrity in the face of rapid technological advancements. It also makes a plea for rigorous research to assess the extent of AI's involvement in the academic literature, evaluate the effectiveness of AI-enhanced plagiarism detection tools, and understand the long-term consequences of AI utilization on academic integrity. An example framework has been proposed to outline a comprehensive approach to integrating AI into Nephrology academic writing and peer review. Using proactive initiatives and rigorous evaluations, a harmonious environment that harnesses AI's capabilities while upholding stringent academic standards can be envisioned.

Current State and Future of Research in Nephrology.

The focus of this article is to review the available funding opportunities for the nephrology workforce at all career levels and review the current challenges involved in the career of a physician-scientist. While the scarcity of nephrology fellows for training programs is a continuing challenge, increased funding for the National Institutes of Health is encouraging particularly for early career investigators. In addition to National Institutes of Health funding, other funding sources are also discussed as they provide much needed bridge funding during key transition periods for young careers. Recent initiatives such as the Advancing American Kidney Health, KidneyX, and National Institute of Diabetes and Digestive and Kidney Diseases' Kidney Precision Medicine Project offer new research opportunities for bringing much needed innovation to improve lives of people with kidney diseases. The time is now for us to seize the opportunity and ensure that a strong workforce will be able to take advantage of these potential game changers for nephrology.

Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era?

BACKGROUND: Although renal replacement therapy prevents death from uremia, survival among patients with acute and chronic kidney diseases (CKD) remains an imperative concern. The expected life span of US dialysis patients 60-64 years of age is approximately 4.5 years; this is similar to that of patients with lung cancer. Despite substantial progress in many medical specialties over the past decades (e.g., notable reductions in myocardial infarction, stroke, and mortality rates in the general population), survival among dialysis patients has not improved significantly over the same period. A few decades ago, HIV infection and AIDS were pretty much a death sentence. Because of progress in HIV treatment, now it can be controlled with a daily pill, and ongoing research is pushing treatment even further and controls the virus with longer-acting treatment. A cure is no longer impossible for HIV and other viral infections such as hepatitis B and C and many malignancies, but so far there is no cure for CKD. SUMMARY: Billions of dollars have been spent on kidney disease research in the past decades, with no tangible progress in clinical practice. The challenges of improving the quantity and quality of trials in nephrology are enormous. The number of randomized controlled trials (RCTs) published in nephrology is lower than that in other medical subspecialties, and most of the big RCTs in nephrology yield negative results. Nephrology studies evaluating hard clinical endpoints or surrogate endpoints are scarce. KEY MESSAGE: Herein we discuss the slow progress in nephrology research that has impacted clinical practice over the last couple of decades and highlight the major obstacles, challenges, and potential solutions.