Fostering Scientific Innovation to Impact AKI: A Roadmap from ASN’s AKINow Basic Science Workgroup

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In 2020, the American Society of Nephrology (ASN) convened AKINow as a longitudinal initiative to promote excellence in the prevention and treatment of AKI. AKINow’s interests span fundamental research, provider education, and patient advocacy. Here, we describe current efforts of AKINow’s Basic Science Workgroup to foster innovation in AKI research. Recent investments in kidney research have triggered overlapping waves of progress that are beginning to benefit kidney patients. Advances in transplantation stand alongside breakthroughs in the genetics of nephrotic syndrome and the pharmacological treatment of CKD. These and other achievements raise hope for new ways to recognize and thwart nascent kidney injury, accelerate intrinsic repair mechanisms, and restore kidney health. In the area of AKI, the scope of potential effect can be described succinctly: AKI affects more than 13 million people worldwide every year, contributing to nearly 2 million deaths annually (1). Novel technologies, increased collaborations, and the entry of new participants into kidney research will be necessary to reduce these staggering numbers. Leveraging shared interests with patient advocates, investigators within and outside traditional nephrology, and many other stakeholders, our workgroup has developed an AKI innovation roadmap composed of several achievable proposals—described below—that together could foster a community of AKI innovators. An Open Access Online Journal Club Platform Discussion, debate, and dissemination are critical to weave new findings into the evolving tapestry of AKI knowledge. An AKINow sponsored Online Journal Club supported by the ASN should provide a forum for timely interrogation of state-of-the-art research. A platform open to ASN members and nonmembers alike will regularly unite expert authors and reviewers with community participants ranging from patients and trainees to investigators in unrelated areas. The journal club will utilize ASN’s webinar format that has been highly successful for coronavirus disease 2019 updates. A volunteer committee of ASN members will survey kidney journals, general interest publications, and other specialties to identify timely articles, for example on xenotransplanation. Each journal club will be hosted and moderated by two members of AKINow and in collaboration with other ASN committees. Each meeting will require one-click registration but will be free of charge. We aim to have first and/or senior authors present the findings and to foster a large, diverse, and highly interactive audience. The entirety of each journal club will last one hour, and we aim to organize four sessions per year. With success, this platform can and should expand quickly beyond AKI to incorporate other areas of nephrology. Democratizing Data Science through Interactive Pedagogy Data science is transforming fields ranging from political science to finance, commerce, and medicine. Democratization of data access and data science literacy could simultaneously unleash new advances and enhance the rigor of nephrology research (2). Furthermore, it is crucial to empower young minds with the correct tools to be able to analyze data appropriately and critically assess the quality of analyses presented by others. To improve the quality of published data, elevate data science literacy, and increase participants in nephrology research, we envision an interactive data science bootcamp series. Instruction would be hands-on and interactive. An initial offering could focus on matriculating a cohort of participants new to statistics and programming through the basics of data manipulation and analysis with different statistical language software such as Python and R. In conjunction with traditional didactic sessions, these bootcamps will also offer practical hands-on experience with interactive modules and use of preexisting real-world kidney datasets to offer relevant coding experience. The program will be configured to enhance learning via three main facets: instructor-led learning, interactive dataset-based learning, and student-student interaction (Figure 1). This format will expand beyond the traditional classroom to offer a rich learning environment that will build a community of learners in nephrology. Important goals of these mini courses would be to mitigate hesitancy around coding and large datasets, convey principles of rigorous analysis, and build confidence for participants to discuss hypotheses and analytical approaches with members of their home institutions. With success, the platform could expand to more complex analyses or even topical areas such as bioinformatics.Figure 1.: An American Society of Nephrology (ASN) hosted interactive educational series to increase literacy in data science. We propose an interactive data science bootcamp series that will utilize instructor-led learning, foster student-to-student interactions, and promote interactive analysis of large databases. This bootcamp series will emphasize the development of basic data science skills and implementation with statistical software.An Open Access Omics Data Warehouse Advances in our ability to interrogate kidney tissue and other biospecimens from both patient volunteers and experimental disease models offer an unprecedented opportunity to catalyze innovation in kidney health. Multiomic techniques include genomics, epigenomics, bulk transcriptomics, spatial transcriptomics, single-cell transcriptomics, proteomics, and metabolomics. The combined power of these approaches to understand changes at the levels of DNA, RNA, protein, and chemistry—further refined by anatomy, cell type, and temporal progression of disease—may yield novel markers of kidney disease and new insights into mechanisms amenable to therapeutic restoration of kidney health (Figure 2). Within nephrology, several consortia are already pursuing publicly available multiomic interrogation. One highly accessible opportunity for ASN is to increase traffic to such existing resources by providing links and curated introductory content from the creators.Figure 2.: An ASN hosted multiomics platform to catalyze innovation and education in kidney health. ASN journals increasingly publish research that utilizes multiple omics approaches. We propose a data warehouse capacity hosted by ASN to make omics results from its affiliated journal broadly available for independent analyses.ASN could also consider going further by creating an open-access, one-stop, tractable, online searchable data warehouse that can accelerate the translation of research from disease models to actual patients. Increasing accessibility for researchers with relatively scarce resources—including those from developing countries—will promote ASN’s initiative to disseminate equitable distribution of knowledge to promote kidney health. Development of a searchable -omics repository that can be either downloaded or analyzed in the ASN environment could foster a global, collective, and interactive research community not only for academic researchers but also other groups. This resource could also facilitate education in multiomics data analysis, for example by hosting hack-a-thons and didactic webinars, thereby helping to attract prospective trainees into our field. Initially, we envision this unique warehouse to become a site of choice for data deposition by investigators publishing in ASN-affiliated journals. Aligning Discovery to Drug Development Health care costs and resource utilization for managing hospitalized patients with AKI are estimated to be between $5.4 and $24 billion annually (3). However, the investment of research funding from the National Institute of Health for kidney disease including AKI is significantly lower compared with the support for cancer, diabetes, heart disease, or HIV/AIDS (4). The coronavirus disease 2019 pandemic has highlighted the effect of kidney involvement in hospitalized patients requiring RRT that resulted in unprecedented stress on major health systems. Recognizing the significant burden of AKI and CKD, a positive recent trend is the increasing interest in pharmaceutical companies and venture capitalists to consider funding for these conditions. Multiple areas are poised for investments, including preventive strategies for AKI, rapid and real time monitoring of kidney function, and developing pro-recovery interventions. The exciting developments for new CKD therapies such as sodium/glucose cotransporter 2 inhibitors and the overlapping pathways between AKI and CKD offer new opportunities for a developmental path for such innovative therapeutic approaches. In this regard, the Kidney Health Initiative (https://khi.asn-online.org/), a public-private partnership between the ASN and the US Food and Drug Administration and more than 100 industry members, will play a critical role in catalyzing innovation for patient-centered therapies for AKI. Among the charges of the Kidney Health Initiative is the collaborative re-examination and development of regulatory milestones that can facilitate clinical development of drugs, diagnostics, devices, and other patient care innovations. Finally, a key transition from discovery to drug development is how to apply animal models of AKI in the study of human AKI (5,6). Whereas clinical trial design is crucial in establishing the efficacy of a drug in the prevention or treatment of AKI, identifying meaningful molecular targets is of paramount importance. The traditional approach is to identify rodent biologic targets, test in animal models, and validate in clinical trials. A more useful approach may be to determine molecular targets in humans, test in relevant animal models, and then validate in clinical trials (7,8). Omics analysis of human molecular targets and identification of endophenotypes (9) will be facilitated by the National Institutes of Diabetes and Digestive and Kidney Diseases’ Kidney Precision Medicine Project (https://www.kpmp.org/), which is aimed at identifying critical pathways and targets for novel therapies. Rather than the traditional linear path of bench to bedside, a recursive cycle that starts at the bedside, goes to the bench, and returns to the clinic offers new promise that AKI discoveries will successfully translate to patients. Summary The individual and societal costs of AKI remain astonishing. The future success of AKI innovation hinges on our collective ability to incorporate new technologies, increase collaborations and dialog, and lower the barriers for new entrants into the field. ASN’s AKINow Basic Science Workgroup seeks to foster a community of AKI innovators. To this end, we have developed a roadmap of achievable initiatives around knowledge dissemination, data science literacy and data access, and new ways to align discovery to clinical development. As each component of this first-generation roadmap is explored and implemented, we continually seek input from AKI’s diverse set of stakeholders (twitter handle @ASN_AKINow). A posture of impatience for progress will remain essential to achieve the goal of reducing the burden of AKI. Disclosures A. Agarwal reports consultancy for Akebia Therapeutics and Dynamed; serving on the medical advisory board of Creegh Pharmaceuticals; ownership interest in Creegh Pharmaceuticals and Goldilocks Therapeutics, Inc.; research funding from Genzyme/Sanofi Fabry Fellowship Award; honoraria from the University of Maryland, University of Toledo, and University of Virginia; having a pending patent that describes small molecule inducers of heme oxygenase-1 for the treatment of acute and chronic kidney disease; being on the editorial board of the American Journal of Physiology-Renal Physiology, Kidney International, and Laboratory Investigation; being invited to serve on the advisory board of Goldilocks Therapeutics; serving on the advisory boards of Alpha Young, LLC, Angion, Creegh Pharmaceuticals, and Zydus; and being the spouse of the President for Women in Nephrology (2020–2022). J. Cerda reports ownership interest in New York Nephrology (shareholder); an advisory or leadership role with the American Society of Nephrology (chair of the AKINow Initiative), International Society Nephrology (AKI Committee and co-chair of the 0by25 Initiative), International Society of Nephrology (chair of the Advocacy Working Group); and other interests or relationships with the ASN AKINow Initiative (associate director of the 0by25 Initiative), the ASN Online AKI Community (member), and the International Society of Nephrology. M.D. Okusa reports employment by the University of Virginia Health System; consultancy for HemoShear and Janssen; ownership interest in AAPL; Allstate (ALL), Citigroup (C), Nextera Energy (NEE), Pepsico (PEP), Walmart (WAL); BABA, AIG, BK, BCS, BP, CAH, CRRFY, CI, C, CMCSA, CRH, CVS, ERJ, EMR, ENIC, ENGIY, E, EBKDY, FNMA, FDX, FISV, FLEX, FMX, F, FCX, GE, GD, GEBHY, GSK, GRFS, HAL, HCA, HDELY, HMC, INGR, JSAIY, JPM, KGFHY, LH, MCK, MRK, MU, MHK, OMF, OGN, PFE, PNC, PUBGY, REPYY, RDS B, SNY, SBGSY, STT, SMFG, VIV, TSCDY, TXT, TTE; research funding from AM Pharma/Pfizer and the National Institutes of Health (research grant); honoraria from the Cleveland Clinic Foundation, the Korean Society of Nephrology, the University of Tokyo, and UptoDate; patents or royalties from the University of Virginia Patent Office; an advisory or leadership role for NIDDH/NIDDK Data and Safety Monitoring Board; and other interests or relationships with the John Bower Foundation (travel). S.M. Parikh reports consultancy for Aerpio, Alkermes, Astellas, Boehringer Ingelheim, Cytokinetics, Entrada Therapeutics, Flagship Pioneering, Janssen, Leerink Swann, Merck, Mission Therapeutics, Mitobridge, NovMeta, and Pfizer; research funding from Baxter; patents or royalties from UpToDate; an advisory or leadership role with the Journal of the American Society of Nephrology and Kidney360; and other interests or relationships with the American Association of Physicians, American Society for Clinical Investigation, the American Society of Nephrology, and the International Society of Nephrology. All remaining authors have nothing to disclose.