A Core Outcome Set for Trials in Glomerular Disease

A Report of the Standardized Outcomes in Nephrology–Glomerular Disease (SONG-GD) Stakeholder Workshops

Abstract

Visual Abstract

Background and objectives 

Outcomes reported in trials in adults with glomerular disease are often selected with minimal patient input, are heterogeneous, and may not be relevant for clinical decision making. The Standardized Outcomes in Nephrology–Glomerular Disease (SONG-GD) initiative aimed to establish a core outcome set to help ensure that outcomes of critical importance to patients, care partners, and clinicians are consistently reported.

Design, setting, participants, and measurements 

We convened two 1.5-hour workshops in Melbourne, Australia, and Washington, DC, United States. Attendees were identified purposively with 50 patients/care partners and 88 health professionals from 19 countries; 51% were female. Patients and care partners were from the United States, Australia, and Canada, and had experience of a glomerular disease with systemic features (n=9), kidney-limited nephrotic disease (n=9), or other kidney-limited glomerular disease (n=8). Attendees reviewed the results of the SONG-GD Delphi survey and aims of the workshop and then discussed potential core outcomes and their implementation in trials among moderated breakout groups of eight to 12 people from diverse backgrounds. Transcripts of discussions were analyzed thematically.

Results 

Three themes were identified that supported the proposed core outcomes: limiting disease progression, stability and control, and ensuring universal relevance (i.e., applicable across diverse populations and settings). The fourth theme, preparedness for implementation, included engaging with funders and regulators, establishing reliable and validated measures, and leveraging existing endorsements for patient-reported outcomes.

Conclusions 

Workshop themes demonstrated support for kidney function, disease activity, death, life participation, and cardiovascular disease, and these were established as the core outcomes for trials in adults with glomerular disease. Future work is needed to establish the core measures for each domain, with funders and regulators central to the uptake of the core outcome set in trials.

Introduction

Problems with the selection and reporting of outcomes in trials are well recognized in many fields (^1–5) and can be addressed by developing core outcome sets. A core outcome set is a consensus-derived, minimum set of outcomes to be reported in all trials in a clinical field (⁶). Initiatives such as Outcome Measurement in Rheumatology (OMERACT), Core Outcomes Measures in Effectiveness Trials (COMET), and Standardized Outcomes in Nephrology (SONG) formed to develop core outcome sets and refine the methods used to identify them.

Glomerular diseases are a heterogeneous group of conditions that have in common varying degrees of impaired kidney function, proteinuria, fluid retention, and hypertension (⁷). Patients with glomerular disease have higher risks of kidney failure (⁸), cardiovascular disease (^9–11), and mortality (^12–14) and may experience serious adverse treatment effects, including infection, diabetes, malignancy, and infertility (¹⁵). Glomerular diseases and their treatment can be unpredictable; disruptive to daily life; cause debilitating symptoms, including fatigue and swelling (¹⁶), poor mental health (¹⁷); and reduce functioning and quality of life (¹⁸,¹⁹). However, these important and shared effects of glomerular diseases and their treatments are not always reported in trials.

In particular, patient-reported outcomes, such as fatigue, cognitive impairment, anxiety, isolation, and loss of independence, are common and troubling to patients with glomerular disease (²⁰). These outcomes are often omitted from trials, and few validated, patient-reported outcome measures exist for this population (²¹,²²). Outcomes such as proteinuria, kidney function, and kidney failure are reported but use varying definitions and cutoffs, or are part of composite outcomes, thus reducing our ability to compare treatments (^23–25). Surrogate outcomes are often used in trials, due to the slow progression of many glomerular diseases, to avoid large sample sizes and long follow-up times (²⁶).

Launched in 2018, the SONG–Glomerular Disease (SONG-GD) initiative aimed to develop a core outcome set for trials in adults with glomerular disease (²⁷). We convened two international stakeholder workshops to discuss potential core outcomes among patients with glomerular disease, their care partners, and health professionals. Potential outcomes were previously identified using standardized consensus methods, with diverse international input, that consisted of 16 focus groups with patients and care partners held in four countries (²⁰) and an online Delphi survey of 700 participants from 54 countries (²⁸). This report summarizes the discussions at the two stakeholder workshops, the input from nonattending contributors, and outlines the SONG-GD core outcome set.

Materials and Methods

Overview of SONG-GD Consensus Workshops

We convened two international SONG-GD consensus workshops during the World Congress of Nephrology in Melbourne, Australia (April 2019), and the American Society of Nephrology (ASN) Kidney Week in Washington, DC, United States (November 2019). The workshops sought to elicit stakeholder feedback around the selection and implementation of a potential core outcome set for trials in glomerular disease using recommended methods (²⁹,³⁰). Core outcomes were proposed on the basis of the results of an international two-round Delphi survey that was completed by patients aged ≥18 years (n=379), care partners (n=37), and health professionals (n=288) from 54 countries with experience or expertise in glomerular disease (²⁸). The Delphi method is a multiround survey used to achieve consensus across stakeholder groups. Participants review all results from the preceding round and revise their responses in each new round. In round 2, critically important outcomes were defined as those outcomes that, for both patients/care partners and health professionals, had a mean Likert score of eight or more (on a nine-point scale), a median of nine, and >75% of participants scoring the outcome “critically important” (scores seven to nine) in both groups. Workshop attendees reviewed and discussed these critically important outcomes, including kidney function, need for dialysis or transplant, relapse/remission, proteinuria, death, life participation, cardiovascular disease, and infection.

Participants and Contributors

We invited patients with a primary or secondary glomerular disease who were ≥18 years (²⁷), their care partners, and health professionals (nephrologists, researchers, allied health, regulators, funders, policy makers, and industry representatives) to attend the workshop. Patients and care partners were invited to be coinvestigators if they had participated in previous SONG-GD phases or social media. Targeted invitations were sent to individuals holding leadership or decision-making roles in professional societies (e.g., International Society of Nephrology [ISN], Cochrane), advocacy groups (e.g., NephCure Kidney International), regulatory bodies (e.g., Food and Drug Administration [FDA], European Medicines Agency [EMA], Australian Pharmaceutical Benefits Scheme), funding agencies (e.g., National Institutes of Health [NIH], National Health and Medical Research Council [NHMRC] of Australia), policy organizations (e.g., Australia Department of Health, Australia Institute of Health and Welfare), clinical guideline groups (e.g., Kidney Disease Improving Global Outcomes [KDIGO]), registries (e.g., Cure Glomerulonephropathy; Nephrotic Syndrome Study Network, Toronto; and British Columbia Glomerulonephritis Registries), and journal editors.

In total, 50 patients/care partners and 88 health professionals attended one or both workshops (n=138; Table 1). Thirteen patients, seven care partners, and 49 health professionals from 17 countries attended workshop 1 (Melbourne, n=69); 18 patients, 13 care partners, and 58 health professionals from 13 countries attended workshop 2 (Washington, DC, n=89). Seventy-one attendees (51%) were female. The names and affiliations of all attendees and contributors are provided in Supplemental Summary 1. Patients and care partners were from the United States (n=30), Australia (n=16), and Canada (n=4). Nine patients had a glomerular disease with systemic features (e.g., lupus, ANCA-associated vasculitis), nine had a kidney-limited nephrotic disease (e.g., FSGS, membranous nephropathy), and eight had other kidney-limited glomerular diseases (e.g., IgA nephropathy). Four patients did not identify their disease. Health professionals were from 19 countries including the United States (n=27); Australia (n=25); Canada (n=8); United Kingdom (n=6); France (n=3); Hong Kong (n=3); Germany (n=2); and one each from Brazil, China, Czech Republic, Greece, India, Italy, Lithuania, Mexico, Netherlands, Singapore, Sweden, and Vietnam. Nonattending investigators gave feedback on the preworkshop materials and draft report by email.

Table 1. - Attendee characteristics of the Standardized Outcomes in Nephrology–Glomerular Disease consensus workshops

Characteristics	n (%) (N=138)
Female sex	71 (51)
Country
United States	57 (41)
Australia	41 (30)
Canada	12 (9)
United Kingdom	6 (4)
France	3 (2)
Hong Kong	3 (2)
Germany	2 (1)
Netherlands	2 (1)
Sweden	2 (1)
Other a	10 (7)
Patients b	30 (22)
Glomerular disease subtype
Glomerular disease with systemic features	9 (7)
Kidney-limited nephrotic disease	9 (7)
Other kidney-limited glomerular disease	8 (6)
Not specified	4 (3)
Care partners b	20 (14)
Health professionals b	88 (64)
Role
Academic nephrologist	62 (45)
Researcher	11 (8)
Industry	5 (4)
Policy or guidelines	4 (3)
Patient advocacy	4 (3)
Regulator or funder	2 (1)

^aBrazil, China, Greece, India, Italy, Czech Republic, Lithuania, Mexico, Singapore, and Vietnam.

^bOf the 162 people invited to the World Congress of Nephrology workshop, 69 attended, with nonattending reasons given as logistic/resource constraints (56), initial nonresponse (25), failure to attend (10), and lack of interest (2). Of 168 invited to the American Society of Nephrology workshop, 89 attended, with nonattending reasons given as logistic/resource constraints (41), initial nonresponse (28), and failure to attend (10).

Workshop Program and Process

Investigators received the programs and materials 1 week in advance of the workshops (Supplemental Appendix 1). In each of the 1.5-hour workshops, we described the SONG-GD process and presented the preliminary results of the SONG-GD Delphi survey. Participants were allocated to seven breakout groups in Melbourne and eight breakout groups in Washington, DC, each consisting of eight to 12 members. Each group included patients/care partners and health professionals with various roles to ensure input and knowledge exchange from stakeholders with diverse experiences and perspectives. Every group had a trained facilitator moderating 35-minute breakout discussions using a question guide (Supplemental Appendix 2), and one or more members from the SONG-GD steering group or executive committee were present to clarify any discussion points, as needed.

Facilitators asked participants to consider and discuss the potential core outcomes that were identified in the SONG-GD Delphi survey. Core outcome sets should consist of three to five outcome domains (including at least one patient-reported outcome capturing how patients feel or function) that are feasible to measure and report in all trials (²⁹). Therefore, participants reflected on the critically important outcome domains for both patients and health professionals that were identified in the SONG-GD Delphi survey: kidney function, need for dialysis or transplant, remission/relapse, death, life participation, and cardiovascular disease. For the plenary discussions, the cochairs (D.C., L.L.) called on a spokesperson from each breakout group to summarize their discussion.

All breakout and plenary discussions were audio recorded and transcribed verbatim with the attendees’ consent. Transcripts were entered into HyperResearch (version 4.0.3, ResearchWare Inc., Randolph, MA) to assist coding and were analyzed thematically. The first author read the transcripts line by line and inductively identified and coded concepts into themes reflecting stakeholder perspectives that underpinned the proposed core outcomes for trials in glomerular disease. Themes were discussed among facilitators (A.Baumgart, S.A., E.A., S.A.C., J.C.C., M.H., M.N., N.S.-R., A.T., A.K.V.) and the SONG coordinating committee to ensure the range and depth of discussions were captured.

Results

Summary of Workshop Discussions

On the basis of the discussion across the two workshops, we identified four themes relevant to the selection of a core outcome set for trials in glomerular disease: limiting disease progression, stability and control, ensuring universal relevance, and preparedness for implementation. The coding tree developed in the analysis consisted of these themes and their subthemes (described below); illustrative quotations are presented in Table 2. Data saturation was achieved because no new subthemes appeared during the second workshop. The SONG-GD core outcome domains are shown in Figure 1 (tier 1). Core outcome definitions and recommendations from the workshops are provided in Table 3.

Figure 1.: The Standardized Outcomes in Nephrology–Glomerular Disease (SONG-GD) core outcome set to be reported in all trials in adults with glomerular disease.

Table 2. - Selected quotations from the workshop discussions illustrating and summarizing each theme

Theme	Quotations
Limiting disease progression
Minimizing disease-mediated kidney injury	“Is there something going on that you can reverse or you can stop? If…your GFR is 30, then apart from trying to prevent further progression, there is not a lot we can do. But if you’ve got an active glomerulonephritis, there is a reversible process going on.” (Clinician-researcher, ASN, group 4) “Your disease could be active and progressing, or it could be inactive but you have sustained so much damage it is progressing anyway.” (Clinician, ASN, group 7) “…proteinuria [is] the mirror of injury, and injury is different than activity.” (Clinician-researcher, ASN, group 5)
Averting vital organ failure and death	“Our goal is to flatten that [eGFR] slope or slow it down…the goal is to prevent the end stage kidney outcome.” (Clinician, ASN, group 3) “Kidneys compensate for renal function until they are really damaged, so symptoms and everything comes when kidneys are almost at the end stage.” (Clinician-researcher, ASN, group 6) “Longevity should be prioritised, whether that is longevity of kidney function or longevity of life.” (Clinician, WCN, group 4)
Stability and control
Addressing daily limitations and distressing harms	“[A] drug might do more for your proteinuria and kidney function but cause more fatigue, or you might have less fatigue but it may be less effective…we have to be able to quantify the quality of life versus the hard outcome measures as well.” (Clinician, WCN, group 6) “If you have got really heavy proteinuria and you get swelling and all these other things that come with it, that is different to measuring a number which tells you something which is a lot more theoretical….It has got different meanings.” (Clinician, ASN, group 2) “It’s the treatment that causes all the problems, like your immune suppressants, you end up picking up everything else that’s around. You end up being fairly unhealthy…not necessarily from kidney disease.” (Patient, WCN, group 6) “It is the side effects of the treatment that render patients completely miserable.” (Clinician-researcher, ASN, group 6)
Reducing unpredictability and upheaval	“We are talking about activity but the other way to say it is stability.” (Clinician-researcher, ASN, group 2) “Disease activity as quality of life. Sort of go hand in hand to me.” (Care partner, ASN, group 1) “All of a sudden, bam. You have come down too far and then you relapse and you’re back up to where you were a year ago. Remission takes ages to get to a good spot, and then relapse takes a week.” (Patient, WCN, group 1) “If [the results are] different, that means there is going to be a follow-up lab, follow-up call, or a follow-up appointment and that is disruptive to the patient…another encounter with the healthcare system … if [they are] stable, that means keep on living your life.” (Clinician-researcher, ASN, group 2)
Ensuring universal relevance
Applicable across diverse populations and settings	“We have [patients] who come up and down, remission and then relapse…we have those who have persistent disease, sometimes persistent and stable, sometimes persistent and progressive…when you talk about relapse and remission it is two extremes, but it does not capture the possibilities of the whole patient experience…when you are thinking about a core outcome measure, you have to try to think about how it applies to everyone.” (Clinician-researcher, ASN, group 8) “Disease activity is a more encompassing term. Just relapse/remission sort of seems binary, whereas disease activity again is a spectrum, like very active, less active. I think it’s broader and would be better for thinking about all glomerular diseases.” (Patient, ASN, group 6) “Maybe kidney function is the most portable of the outcomes depending on the disease as well as the country and the situation and if they start dialysis sooner rather than later.” (Clinician-researcher, ASN, group 6) “[GFR] captures everybody as opposed to just subsets.” (Clinician, ASN, group 6)
Living well	“You learn from patients that life quality is much more important than death…no one wants to face their mortality, but how you live your life is more important than thinking about death.” (Clinician-researcher, ASN, group 1) “Death is part of life participation, because you cannot participate in life without being alive.” (Patient, ASN, group 6) “There is an interaction between the two, because if quality of life was really low, then that would affect where you prioritize death. If your quality of life is great, you don’t want to die… they are interlinked with each other.” (Clinician, ASN, group 2)
Preparedness for implementation
Engaging with funders and regulators	“The easy answer is regulatory incentive…collecting a lot of information takes time and money…if the FDA is pre-emptively telling you, this is going to matter… it will affect your approval and possible reimbursement…that’s how you get them more incorporated.” (Researcher, WCN, group 2) “The best way would be for various research bodies and health technology assessment bodies to give [core outcomes] priority, to say that the trials that will be considered more valuable are those that use this framework… then it’ll change practice very quickly.” (Policy maker, WCN, group 7) “Unless person-related outcomes become essential, people are not going to measure them because it is more difficult than measuring serum this or urinary that.” (Clinician-researcher, WCN, group 7)
Establishing reliable and validated measures	“The trouble with life participation is how do you measure it? We still don’t know.” (Clinician-researcher, WCN, group 1) “Disease activity we all agree should be an outcome. The devil will be in the detail of how you measure disease activity as relevant to each of the different diseases.” (Researcher, ASN, group 6) “I don’t actually think we have very good measures of disease activity…for IgA, we have proteinuria but that doesn’t mean the disease is active… we don’t have accurate tools to do that.” (Researcher, ASN, group 6)
Leveraging existing endorsements for patient-reported outcomes	“The 21st Century Cures Act by the FDA made one of the priorities patient insight and patient-reported elements…the FDA is saying to patients…you tell us what matters so we can start designing better trials.” (Researcher, ASN, group 2) “The regulators both from the FDA, the EMA have all mandated that we bring in patient quality of life reported outcomes. The payers… are mandating patient-reported outcomes.” (Industry representative, WCN, group 6)

ASN, American Society of Nephrology; WCN, World Congress of Nephrology; FDA, Federal Drug Administration; EMA, European Medicines Agency.

Table 3. - Definitions and recommendations for establishing the core outcome domains for trials in adults with glomerular disease

Definitions and Recommendations
Definitions of the core outcomes a :
• Kidney function: How well the kidneys remove “waste” from the body and balance salt and fluids (could be measured by creatinine in the blood and GFR)  • Disease activity: Gradual or intermittent injury to the kidney, particularly the filters (i.e., glomeruli), that may be treatable or reversible  • Death: Number of people who die, risk of death, how long the patient will live  • Life participation: Ability to participate in meaningful, daily activities, including socializing, study, or hobbies  • Cardiovascular disease: Disease of the heart and blood vessels (including stroke, heart attack, or heart failure)
Core outcome domains for glomerular disease should:
• Capture major life-threatening outcomes (e.g., death, cardiovascular disease)  • Capture the ability to meaningfully participate in life’s activities  • Consider the distress and disruption to life caused by glomerular disease and its treatments  • Be relevant to major treatment decisions, monitoring, and patient self-management  • Focus on preventing kidney injury and limiting disease progression  • Apply regardless of age, disease type or stage, setting, or country
Implementation of core outcomes requires:
• Recognition and endorsement of critically important patient-reported outcomes  • Identifying or codeveloping valid and reliable core measures with patients  • Identifying disease-specific definitions and measures for disease activity  • Having measures that are feasible to implement in all trials with minimal measurement burden  • Inclusion of core outcomes in trials to be mandated by funders and regulators

^aDefinitions are based on those in the Delphi survey. The definition for disease activity was based on the workshop discussions and Delphi survey analysis.

Limiting Disease Progression.

Minimizing Disease-Mediated Kidney Injury.

Patients and health professionals highly prioritized control of disease-related kidney injury because this was regarded as both the earliest and dominant “pathway” to loss of functional kidney reserve. Disease-mediated injury was likened to a “fire we are trying to put out” that may respond to treatment, “stabilize,” or even be reversible, whereas accumulated scarring was not. Determining reversibility of disease-mediated injury was key in weighing beneficial treatment effects (e.g., stopping progression) against side effects. Discriminating between reversible and irreversible injury could be difficult and often required surrogate markers or kidney biopsy. For both episodic (e.g., ANCA-associated vasculitis) and progressive (e.g., FSGS, IgA nephropathy) patterns of injury, “preservation” of kidney function was critical. Some patients experienced disease-mediated kidney injury as “dreaded” and unpredictable events (e.g., swelling, fatigue), whereas others found it “very difficult to know if you’re in remission or not.” Health professionals focused on minimizing kidney injury (e.g., remission or stability, preventing relapse) with the goal of “maintenance of kidney health in the longer term.”

Averting Vital Organ Failure and Death.

Excretory function (e.g., eGFR) in the absence of acute injury was agreed to be the best available measure for assessing overall kidney health because it applied “across the board” and contained more information than need for dialysis or transplant, which was a “blunt, late measure.” Health professionals felt kidney function and need for dialysis or transplant lay on the “same spectrum”; however, for patients, dialysis and transplant were distinct, distressing, and meaningful events. Need for dialysis or transplant also captured progression not directly from glomerular disease because, at lower levels of kidney function, you can “switch off the activity but the patient continues to decline.” Kidney function and cardiovascular disease were risk factors for each other, and are major causes of morbidity and mortality that participants emphasized should always be captured in trials.

Stability and Control.

Addressing Daily Limitations and Distressing Harms.

Symptoms of glomerular disease, treatment harms, and poor kidney function could cause “diminution in quality of life” and result in patients not “participating in life.” In particular, for some patients, immunosuppressive therapies “cause all the problems” and may “render patients completely miserable.” Patients felt extreme discomfort or “terrible,” which could lead to the inability to complete essential daily tasks, and this was often underappreciated by health professionals.

Reducing Unpredictability and Upheaval.

Patients experienced glomerular diseases as “silent” or “intangible,” with unpredictable and substantial “disruption of life” due to symptoms, treatment effects, and monitoring of kidney function and disease activity. Inability to predict recurrent events and “always putting out fires” provoked anxiety and suffering in patients due to uncertainty and the “ups and downs.” Patients needed to be “confident” in their future planning and, although they often relied on laboratory testing that was “in someone else’s hands,” the results reassured them there would be “no changes” and they could “keep on living [their] life.”

Ensuring Universal Relevance.

Applicable across Diverse Populations and Settings.

Patients and health professionals agreed that, to provide the most benefit to all stakeholders, the core outcomes should be broadly relevant, robust, and, where possible, capture the “whole patient experience.” Kidney function, death, life participation, and cardiovascular disease applied across different conditions, stage of CKD, and life stages. However, the different patterns of glomerular disease and glomerular injury meant existing treatment thresholds for proteinuria and relapse/remission in some diseases were not applicable across all patient populations. Disease activity was identified as a critically important domain across all glomerular diseases that incorporated relapse and remission, although it was suggested that disease-specific definitions and measures would be required.

Living Well.

Death and life participation were “interlinked with each other” and regarded as important to everyone. Patients wanted to know about both survival and life participation when making decisions, because treatments may “improve your disease activity but make your quality of life a lot less.” Fatigue was a key determinant of life participation for some groups (e.g., patients who were nephrotic), but life participation “encompass[ed] a broader scope of disease implications” and was more important in treatment decisions. The ability to participate in life and be as “normal as possible” captured more than absence of disease, but also how patients felt, their functioning, and capacity to get their “life back.”

Considerations for Implementation.

Engaging with Funders and Regulators.

Funders and regulators were viewed as influential in governing the conduct of trials, and they wanted advice about measuring outcomes that were “going to matter” to better determine what “the value of the drug is.” It was suggested that regulators could “change practice very quickly” and “drive behavior” by mandating core outcomes or giving higher priority to trials that included core outcomes because they would provide more relevant information. Funders were said to be more willing to sponsor trials that included core outcomes if they have a “regulatory incentive” or if the outcomes are “going to differentiate” between treatments (e.g., life participation).

Establishing Reliable and Validated Measures.

A major barrier to reporting outcomes such as life participation was the lack of standardized and validated measures. Disease activity would also need to be defined for each glomerular disease. Ideally, the core outcome measures had to be “cheap, …easy” and impose little measurement “burden on the patient,” but must be meaningful to maximize interpretability and utility. Minimizing measurement error, particularly where outcomes are “influenced by other things beyond the intervention” (e.g., life participation, proteinuria), was noted to be critical to avoid inaccurate conclusions about therapeutic effect.

Leveraging Existing Endorsements for Patient-Reported Outcomes.

Attendees recognized there was “much more awareness” and support from regulators (e.g., FDA, EMA), funders, and health professional organizations for patient-reported outcomes who are “now listening to patients” about what matters. Gathering patient and care partner insights to “understand what patients are looking for” in the treatment of their disease will help in the design of better trials. This recognition that outcomes such as life participation are important and best assessed by direct patient report will help motivate researchers to include patient-reported outcomes in trials.

Postworkshop Consultation

The draft workshop report was circulated via email to all participants who were requested to provide feedback within 2 weeks; transcripts were not returned to participants. The proposed SONG-GD core outcome set was distributed to all participants for review and uploaded to the SONG website for general feedback and comment (https://songinitiative.org/projects/song-gd/). The report was revised on the basis of feedback and comments from workshop attendees and contributors. Participants agreed the analysis was consistent with and supported the proposed core outcomes.

Discussion

Kidney function, disease activity, death, life participation, and cardiovascular disease were established as the SONG-GD core outcomes to be reported in all trials in people with glomerular disease. On the basis of consensus, the core outcomes were critically important to all stakeholder groups across different populations and settings for decision making. Kidney function (i.e., kidney excretory function; GFR) was currently felt to be the single most important, overarching indicator of kidney health and functional reserve. Disease activity, rather than relapse/remission, was considered applicable to all glomerular diseases and regarded as the major, potentially treatable, cause of progression, and also responsible for disruptive or troubling symptoms in some patients. Understanding the risks of death and cardiovascular disease was also fundamentally important to patients and clinicians. Life participation was critical to clinical decisions and in evaluating therapies because how patients feel or function when undertaking meaningful life activities was considered alongside mortality risks or disease-modifying benefits. Implementation of these outcomes in trials depended upon identifying meaningful and valid measures for each outcome and was thought to require regulatory and funding agency support for their inclusion in trials.

Kidney function and need for dialysis and transplant captured kidney health differently. Patients felt starting dialysis or having a kidney transplant were discrete, life-altering events, whereas health professionals viewed these events on the continuum of declining kidney function. Patients and health professionals agreed that kidney function quantified early decline in kidney reserve and in advanced stages, and was more relevant across the glomerular diseases, whereas need for dialysis or transplant was a late-stage, binary outcome and less relevant for some diseases (e.g., minimal change disease). The need for dialysis or transplant also captures progression due to causes other than active disease, meaning therapeutic effects that are potentially beneficial in earlier stages of the disease may be obscured. Definitions of kidney failure for trials have recently been established using both clinical and eGFR-based criteria (³¹). Because need for dialysis or transplant would largely be captured by eGFR-based data, kidney function was chosen as a core outcome, with need for dialysis or transplant being acknowledged as important and would likely be included in many trials (i.e., second-tier outcomes).

Patients and health professionals identified disease activity as a core outcome that subsumes relapse/remission, but would require disease-specific definitions. Disease activity was critical to treatment decisions in all glomerular diseases because it represents a potentially more treatable pattern of either persistent or episodic kidney injury, which may also affect life participation. Proteinuria, sometimes as a composite outcome with kidney function, is often used in trials in glomerular disease to dichotomize disease activity into relapse or remission (²⁶). For some glomerular diseases (e.g., ANCA-associated vasculitis, membranous nephropathy), relapse was a meaningful clinical outcome in its own right and, for patients, this was determined by symptoms (e.g., fatigue, swelling), whereas health professionals focused more on lack of proteinuric remission as a surrogate for kidney failure, with proteinuria being endorsed by the FDA for this purpose (^32–34). However, attendees agreed that the binary outcomes of relapse/remission were less relevant to several patient subgroups within and across glomerular diseases and could lead to loss of important data that would be captured by a continuous measure of disease activity.

Patients with glomerular disease, care partners, and health professionals agreed life participation—the ability to participate in meaningful life activities—should be a mandatory patient-reported outcome. Capturing life participation was felt to be critical in understanding key beneficial and adverse treatment effects and was required when weighing treatment options (e.g., infection risks, changes in appearance from immunosuppression). Other relevant outcomes, including treatment harms, should also be reported because core outcome sets do not replace adverse event reporting. Patients and health professionals recognized that, for some glomerular diseases or treatments, specific patient-reported outcomes were important (e.g., fatigue, cognitive function). However, life participation was considered by all stakeholder groups to be the most important patient-reported outcome and relevant across all glomerular diseases. Life participation has been selected as a core outcome for trials in peritoneal dialysis, kidney transplantation, and in children with CKD (^35–37). However, there is a need for reliable, validated, and feasible glomerular disease–specific instruments that capture life participation to be developed or nominated as a core measure.

Cardiovascular disease and mortality have been established as core outcome domains for patients on hemodialysis and peritoneal dialysis, those with a kidney transplant, and in those with polycystic kidney disease, and are now proposed for patients with glomerular disease (³⁵,³⁶,³⁸,³⁹). Health professionals identified cardiovascular disease as a major cause of mortality in adult patients with impaired kidney function from glomerular disease, on the basis of the elevated risk present from early stages of CKD, a risk that is progressively higher with declining kidney function and markedly so with dialysis commencement (^9–11,⁴⁰,⁴¹). Similarly, patients viewed cardiovascular disease as a major life threat but also recognized its potential for having an effect on daily activities, and noted that this would be mostly captured by life participation.

We convened two international stakeholder workshops with diverse input using methods based on the COMET recommendations (³⁰). The candidate core outcomes that informed workshop discussions were identified in previous work that used methodologic triangulation (i.e., focus groups, Delphi survey). There were some limitations. Most health professionals were conference delegates, and patients and care partners were English speaking and from three high-income countries. We did not have input from regulators and funders from all continents. Therefore, the extent to which the findings reflect the perspectives of those from other countries, health care systems, or resource settings is uncertain.

The SONG-GD core outcomes of kidney function, disease activity, death, life participation, and cardiovascular disease are of critical importance to patients, care partners, and health professionals and should be reported in all trials in adults with glomerular disease (Figure 1). The next phase of SONG-GD will determine the core measures using the methods recommended by COMET and OMERACT (²⁹,³⁰,⁴²), focusing initially on disease activity. The SONG initiative is establishing core measures for life participation, cardiovascular disease, and death (survival) for trials in hemodialysis and peritoneal dialysis. Ideally, outcome definitions and measures are simple, easily interpreted, and applicable across different resource settings, interventions, and populations (³¹). Ultimately, the SONG-GD core outcome set will improve the relevance and strength of the evidence base that informs treatment decisions.

Disclosures

S. Anumudu reports serving as an ASN Public Policy Committee member and a Renal Physicians Association board member, Government Affairs Committee vice chair, and Membership and Education Committee member and receiving honoraria from KDIGO Controversies Conference on BP and volume management in dialysis (travel expenses reimbursed) and from St. George’s University (occasional honoraria for helping with student events or webinars as student counselor and alumni admissions mentor program). E. Au reports serving as a member of Australia and New Zealand Society of Nephrology, ISN, The Transplantation Society, and Transplantation Society of Australia and New Zealand; serving as a scientific advisor or member of Kidney360 and Transplantation; and having ownership interest in Medibank Australia. A. Bagga reports having consultancy agreements from Novartis for serving on a steering committee on hemolytic uremic syndrome. S.J. Barbour reports having consultancy agreements with Achillion, Alexion, Inception Sciences, Novartis, and Visterra; receiving research funding from Alexion and Roche; and receiving honoraria from Alexion and Roche. J. Barratt reports having consultancy agreements with Alnylam, Astellas, BioCryst, Calliditas, Chinook, Dimerix, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics, and Visterra; receiving research funding from Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline (GSK), Novartis, Omeros, Travere Therapeutics, and Visterra; and serving as on the editorial boards of CJASN, Clinical Science, Glomerular Diseases, and Kidney International. I. Boletis reports serving on the editorial boards for International Clinical Case Journal and Transplantation Proceedings. S.A. Carter reports having ownership interest in Commonwealth Serum Laboratories Limited. D.J. Caster reports having consultancy agreements with, and receiving honoraria from, Aurinia, Calliditas, Chinook, GSK, and Travere (previously Retrophin); serving on speakers bureaus for Aurinia and GSK; serving on the editorial board for Glomerular Diseases, and as a scientific advisor or member of Lupus Foundation of America Medical Scientific Advisory Counsel; and having other interests/relationships with NIH via grants K08 1K08DK102542 and R01 1RO1DK126777. D. Cattran reports receiving research funding from Alnylam; having consultancy agreements with Alnylam, Calliditis, Chemocentryx, Principia, and Reistone; receiving honoraria from Calliditis, Kyowa Hakko Kirin Co., and Principia; having other interests/relationships with Chemocentryx and Novartis; and serving as a scientific advisor or member of Kidney International, NephCure, SONG-GD, and UpToDate. Y. Cho reports receiving research funding from Baxter Healthcare and Fresenius Medical Care; receiving honoraria from Baxter Healthcare, Fresenius Medical Care, and Genzyme; and serving as clinical trialist and chair of the Australasian Kidney Trials Network Peritoneal Dialysis Working Group, and as a member of the coordinating committee for SONG. R. Coppo reports having consultancy agreements with Amgen, Argenx, Calliditas, Novartis, Reata, and Travere; receiving honoraria from Amgen, Argenx, Calliditas, Novartis, and Travere; being employed by Fondazione Ricerca Molinette; serving as a scientific advisor or member of the ISN Council and on the editorial board for Nephrology Dialysis Transplantation; and serving as an associate editor of Pediatric Nephrology. J.C. Craig reports serving on the editorial boards of Clinical Epidemiology and Diagnostic and Prognostic Research, as coordinating editor of Cochrane Kidney and Transplant, and as vice president of Flinders University. F.C. Fervenza reports having consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; receiving research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; serving as a scientific advisor or member of JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate; being employed by Mayo Clinic; and receiving honoraria from UpToDate. J. Floege reports receiving honoraria from Amgen, Astellas, Bayer, Calliditas, Novo Nordisk, Omeros, Travere, Vifor, and Visterra; having consultancy agreements with Amgen, Bayer, Calliditas, Novo Nordisk, Omeros, Travere, Vifor, and Visterra; serving on speakers bureaus for Amgen and Vifor; and serving as a scientific advisor or member of Calliditas, Omeros, and Travere. T. Gutman reports serving on the Patient-centered Research Network coordinating committee and on the SONG initiative coordinating committee (no financial relationships). M.A. Hladunewich reports having consultancy agreements with Alnylam Pharmaceuticals; receiving research funding from Calliditas Therapeutics, Chemocentryx, Ionis, Pfizer, and Roche; having other interests/relationships with Glomerular Disease Ontario Renal Network as medical lead; and serving as a scientific advisor or member of Kidney International and UpToDate. J.J. Hogan reports receiving research funding from Achillion (as site principal investigator [PI] for clinical trial in C3 glomerulopathy), Boeringer Ingelheim (for Transformative Research in Diabetic Nephropathy [TRIDENT] study for diabetic nephropathy), Calliditas (as site PI for clinical trial in IgA nephropathy), Complexa (as site PI for clinical trial in FSGS), Gilead, GSK, NIH (for study in membranous nephropathy and as site PI for the Belimumab With Rituximab for Primary Membranous Nephropathy [REBOOT] study in membranous nephropathy), Omeros (as site PI for clinical trial in IgA nephropathy), Regeneron, and Retrophin (as site PI for the Efficacy and Safety of Sparsentan [RE-021], a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis [FSGS]: A Randomized, Double-blind, Active-Control, Dose-Escalation Study [DUET] and a Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS [DUPLEX] Studies in FSGS); having consultancy agreements with, and receiving honoraria from, Alexion, Aurinia, Calliditas, GSK, Kaneka, Kezar, and Travere; being employed by Janssen: Pharmaceutical Companies of Johnson and Johnson; and receiving royalties for patent (pending) as coinventor (WO2019213434A1) and author royalties from UpToDate.com for topics on calcium/phosphate balance and monoclonal gammopathies of renal significance. A.R. Kitching reports serving as a scientific advisor or member of Australian and New Zealand Vasculitis Society; receiving research funding from CSL Limited and Vifor Pharma; having other interests/relationships as a member of the Kidney Health Australia Research Advisory Group; having consultancy agreements with Toleranzia and Visterra; and receiving honoraria from Visterra. R.A. Lafayette reports having consultancy agreements with Alexion Inc., Aurinia, Calliditas Inc., Chinook Inc., Novartis, Omeros Inc., Otsuka Inc., Travere Inc., Vera Inc., and Visterra Inc.; and receiving research funding from Apellis, Calliditas, Chemocentryx, Chinook, NIH, Omeros, Otsuka, Pfizer, Roche, Travere, and Vera. L. Lightstone reports having consultancy agreements with Achillion, AstraZeneca, Bristol Myers Squibb (BMS), GSK, Pfizer, and Roche; receiving honoraria from Alexion, AstraZeneca, BMS, GSK, and Pfizer; serving on speakers bureaus for Alexion and GSK; having other interests/relationships as executive committee member of ISN (2021–2023), deputy chair of the Western Regional Board of ISN, trustee of Kidney Research UK (2018–2022), and clinical expert representing the Renal Association’s response to the National Institute for Health and Care Excellence on single technology appraisal for belimumab in lupus (2020–2021); and serving as a scientific advisor or member of the European Union Executive Committee of the Lupus Nephritis Trials Network and Nature Reviews Nephrology Advisory Board. M. Nataatmadja reports previously receiving travel support from Amgen. J. Radhakrishnan reports receiving honoraria from Angion Biomedica, Aurinia Pharmaceuticals, Equillium Bio, GSK, Reata Pharmaceuticals, Reistone Biopharma, Sanofi Genzyme, and Travere Therapeutics; having consultancy agreements with Angion Biomedica, Aurinia Pharmaceuticals, Equillium Bio, Reata Pharmaceuticals, Reistone Biopharma, Sanofi Genzyme, and Travere Therapeutics; receiving research funding from Bayer and Travere Therapeutics; and serving as a scientific advisor or member of Kidney International and Kidney International Reports. B.H. Rovin reports having consultancy agreements with Alexion, AstraZeneca, Aurinia, Biogen, BMS, Calliditas, Chemocentryx, EMD-Serono/Merck, Genentech, Human Genome Sciences (GSK), Idorsia, Janssen, MedImmune, Morphosys, Novartis, Omeros, Retrophin, RILITE Foundation, Roche, and Vistera; receiving honoraria from Alexion, AstraZeneca, Aurinia, Biogen, BMS, Calliditas, Chemocentryx, EMD-Serono/Merck, Genentech, Human Genome Sciences (GSK), Idorsia, Janssen, Morphosys, Novartis, Omeros, Retrophin, RILITE Foundation, Roche, and Vistera; performing other work with ASN (mostly educational courses), ISN and National Kidney Foundation, and the Lupus Foundation of America; and serving as a scientific advisor or member of ASN Kidney Week, CureGN, KDIGO, Kidney International, Kidney International Reports, Lupus Foundation of America, Nephrology Dialysis and Transplantation, and UpToDate. N. Scholes-Robertson reports having other interests/relationships with the consumer advisory board of BEAT-CKD (Australia) and Rural Kidney Association Inc. (NSW, Australia); serving as a patient editor of Cochrane Kidney and Transplant; and serving as a scientific advisor or member of Rural Kidney Association Inc. (NSW, Australia). H. Trimarchi reports serving as a scientific advisor or member of American College of Physicians, Argentinian Society of Nephrology, ASN, and ISN and having consultancy agreements with, and receiving honoraria from, Calliditas, Chinook, Novartis, Sanofi Genzyme, Travere, and Visterra-Otsuka. H. Zhang reports serving as vice-director of the nephrology committee of the Beijing Society of Medicine, as a board committee member of nephrology of the Chinese Medical Doctor Association and the Chinese Society of Nephrology, on the member of ISN–Advancing Clinical Trials Committee, and as a member of ISN Global Outreach - Sister Renal Centres Committee and having consultancy agreements with Calliditas, Janssen, Novartis, and Omeros. All remaining authors have nothing to disclose.

Funding

S.A. Carter is supported by the NHMRC Postgraduate Scholarship number 1168994. D. J. Caster is supported by NIH grant K08DK102542. Y. Cho is supported by the NHMRC Early Career Fellowship number 1126256. T. Gutman is supported by a NHMRC Postgraduate Scholarship number 1169149. N. Scholes-Robertson is supported by a NHMRC Postgraduate Scholarship number 1190850. A.K. Viecelli received support from the NHMRC Medical Postgraduate Scholarship number 1114539 and a Royal Australasian College of Physicians Jacquot Research Establishment Fellowship.