Reinforcing the Paramount Importance of Graft Outcomes
As expected by participants, graft-related outcomes (graft loss, graft function, acute rejection, and chronic rejection) were the overriding priorities among stakeholders. From the patients’ perspective, graft outcomes were the same—all a threat to graft survival, and the importance placed on this was underpinned by a dread of dialysis. Health professionals drew distinctions between different pathophysiology or causes of chronic rejection.
Prevailing Dread of Dialysis
Graft loss signalled a dominating fear and aversion to dialysis. For patients, this was the top priority over death and a matter of quality of life. Some patients were “willing to risk not surviving a transplant rather than go on dialysis.” For patients, the possibility of graft failure was an ongoing concern and some questioned whether the drugs would threaten graft survival. Health professionals suggested that long waiting times for transplantation explained the high priority given to graft survival, particularly in countries with very limited access to kidney transplantation.
Distilling the Meaning of Graft Function
Patients stated that graft function was equivalent to not requiring dialysis. It was important that the graft was functioning well or working normally. Health professionals noted that graft function may be a “surrogate” of outcomes that were of direct importance (eg, graft survival, hospitalization, well-being) and questioned whether function mattered on its own. They speculated that patients assumed that graft function (ie, creatinine) was an indicator of graft loss and return to dialysis and reasoned that glomerular filtration rate (GFR) did not necessarily change how the patients felt. Change/stability in kidney function was regarded by health professionals as more important than the “absolute” value as some patients may have suboptimal kidney function but remain stable. They suggested that graft function should be defined in a “patient-focused” way.
Terrifying and Ambiguous Terminology of Rejection
Health professionals believed that the term “rejection” carried catastrophic connotations and were aware that patients could misunderstand rejection invariably as graft loss. Also, the notion of rejecting their donor’s kidney implied guilt. Some patients believed that rejection could be managed with medications but if left untreated could result in death. Health professionals elaborated on different pathways and consequences of the different types of rejection such as cellular versus antibody mediated rejection which garnered attention in terms of risk for graft loss; and they speculated that patients may not be aware of these differences. Although some forms of acute rejection were readily treatable, they suggested that it was still an important outcome particularly if there was an equivalence of treatments. Chronic rejection was consistently regarded by health professionals as ill-defined and not easily measurable. However, the uncertainties in the “multifactorial causes…and flimsy biological epidemiological understanding of chronic graft rejection” and lack of effective treatment, was thought to explain the high importance.
Although there were important distinctions among graft-related outcomes, participants suggested that they could be consolidated into 1 domain—graft health, and the specific outcomes may have addressed in the subsequent phrase of developing the specific core outcome measure for graft health. Also, combining graft outcomes into 1 domain would potentially allow for other patient-reported outcomes to be included in the core outcome set.
Reflecting Critical Trade-Offs
Participants reiterated that core outcomes should encompass the trade-offs between graft health and clinical complications of immunosuppression as these were “2 sides of the same coin.” Health professionals emphasized the importance of infection, cancer, and cardiovascular disease as they were the main causes of death, and the main areas of focus for physicians. Kidney transplantation would not cure other comorbidities or complications such as diabetes or cardiovascular disease. One patient said, “I have taken my immunosuppressant drugs for a long time and I have got a lot of side effects. I have got a lot more considerations whether to get my second transplant.” However, participants acknowledged that rare outcomes may be underemphasized by patients who had not experienced that particular outcome.
Contextualizing Mortality
In the Delphi survey, health professionals gave higher importance to mortality than patients/caregivers and this discrepancy suggests a more nuanced view of death.
Inevitability of Death
Patients regarded death as inevitable and an ongoing risk even if they did not want to die. Ultimately, death could not be prevented, whereas, efforts could be made to prevent graft failure. Even if a graft failed, they would survive on dialysis, to which some regarded as worse than death—“everyone has to face death, what I would like to have is a good quality of life rather than to face death.” Some felt they had already “faced” or “cheated” death so it was no longer a primary concern. One patient articulated, “I don’t think we would ever mind that doctors want to avoid death. That’s your point, of being advocates for life. We’re advocates for our own lives.”
Preventing Premature Death
Health professionals emphasized their responsibility to prevent early death, for example death caused by a cardiovascular event immediately posttransplant. They admitted having difficulty accepting death and “frightened of killing someone with immunosuppression.” Also, health professionals were conscious to protect the kidney particularly given the organ scarcity. They cautioned against conceptualizing death as a single endpoint, and advised to distinguish early/unexpected death from expected death relative to the patient’s age.
Ensuring Safety and Quality
For regulators, mortality was a safety issue in drug development though some clinicians urged that this should be “balanced against the potential for drugs to prolong graft function” as it was the top priority for patients and physicians. Also, health professionals routinely included death as a quality parameter. One physician explained, “death within a year at my institution requires a formal debriefing and conversation as to what happened. I was a little surprised that wasn’t number 1.” Some health professionals also highlighted the increased risk of mortality on dialysis.
Imperative to Capture Patient-Reported Outcomes
Making Patient Priorities Explicit
Although quality of life, in terms of both well-being and functioning, were recognized to be implicit in graft-related outcomes and medical complications, the need to explicitly include patient-reported outcomes was undisputed—“we need to elevate quality of life into the core outcome set, to give patients a voice.” This would overtly and comprehensively capture the balance between mortality and graft survival, and quality of life/burden of side effects. Some patients were more concerned about lifestyle impacts due to immunosuppression, rather than the graft function. Quality of life was also regarded as an important measure of success of a graft. Some suggested that rating scales should be designed such that it would address quality of life dimensions that patients prioritized to be most important. Using generic surveys that broadly assessed all domains of quality of life negated the need to develop an exhaustive list, however others noted that there a good parameter for specific transplant related quality of life was lacking, and that quality of life was too vague. They suggested distilling quality of life into the most important dimensions. Stakeholders emphasized the need to be cognizant of cultural sensitivities and relevance if it was to be applied globally, considering cultural differences.
External Mandates
Health professionals also remarked on the increasing focus on patient-reported outcomes among regulatory/funding agencies, and registries. They specifically referenced the US NIH investment into patient-reported outcome measures through the Patient-Reported Outcomes Measurement Information System (PROMIS), US FDA drug approval requirements to include PROMS; new requirement from the CMS Quality and Assurance and Performance Improvement for centres to assess quality of life; and plans in the European Dialysis and Transplant Registry and Australia and New Zealand Dialysis and Transplant Registry to incorporate patient-reported outcomes. Quality adjusted life years also necessitated quality of life measures for policy decisions.
Life Participation
Ability to work was the most important patient-reported outcome domain in the Delphi survey, however, it did not apply across all age groups or life stages, and social systems. Thus, participants suggested expanding the scope to encompass the range of life activities that gave patients a sense of fulfilment, enjoyment, control, and hope. While being able to work provided a purpose and “normality” in life, and encompassed multiple psychosocial aspects, patients/caregivers agreed that this should be broadened to include life activities in view of the expectation that transplant enabled patients to live their life and to do everything they wanted to do. One caregiver noted that the ability to participate in life motivated patients and gave them a reason for overcoming the challenges in living with a transplant. Health professionals also supported widening the scope to life participation with specific suggestions including studying, hobbies, house work, caring for the family, and social activities. Assessing ability to participate in meaningful activities was amenable to a measure that allowed patients to define their goals and milestones, and to capture the impact of symptoms and complications (eg, gastrointestinal problems, pain, sleep disturbance, vision problem). Although other outcome domains such as cognition and depression were important, these were regarded as relevant to achieving life participation.
Specificity to Transplantation
Health professionals were uncertain about assigning priority to outcomes that were not perceived to be directly specific or attributable to transplantation. For example, they argued that depression may not be considered as a core outcome as anyone could have depression and it was not a transplant-related outcome. For skin cancer, 1 participant questioned if people “were ranking by some combination of seriousness and attributable risk (ie, as a sequelae of transplantation), or both,” and hypothesized that higher priority for outcomes may reflect regional variations in risk in the general population eg, the “epidemic of skin cancer in Australia.”
Feasibility and Pragmatism
Achievability of Long-Term Impacts
Although long-term outcomes such as cardiovascular disease and cancer were important, health professionals believed that mandating reporting was difficult to achieve as the time required to show a difference could be extensive and important events such short-term graft loss and mortality (ie, within a year posttransplant) were rare. Trials were predominantly short-term. Also, in some countries (such as the Philippines), many kidney transplant recipients were lost to follow up in clinical settings. Health professionals suggested considering interim outcomes such as biomarkers, or diabetes or blood pressure as predictors of cardiovascular disease. However, they understood that “patients may want outcomes that might not be captured within a short period of time and satisfy the requirements set by regulatory agencies,” and advocated for outcomes relevant to patients with other outcomes selected for specific trials. The recent changes in funding structures, namely in the UK, supporting long-term trials, and requirements to link trials with national registries were also noted. Health professionals urged for more efforts to persuade industry as well as to partner with funding agencies to support longer-term trials.
Responsiveness to Interventions
Some health professionals were convinced that outcomes should be selected based on potential responsiveness to the interventions, and outcomes relevant to a trial of immunosuppressive agents, lifestyle interventions, surgical techniques or organ perfusion would differ. However, core outcome domains were emphasized to be about relevance to decision making. Although triallists may want to know whether an intervention works, end-users ie, patients and clinicians, want to whether the intervention affects the outcomes they regard as important. Primary outcomes may be selected on feasibility, and appropriateness for the intervention, but the omission of outcomes that stakeholders regard as critical could not be justified.
Recognizing Gradients of Severity
Health professionals were concerned that some outcome domains were broad and encompassed multiple outcomes with a spectrum of consequences, and this may have had implications for how participants rated its importance. For example, surgical complications could range from minor complications to those that required additional surgical intervention. Infections could range from a urinary tract infection to a more serious infection such as CMV. However, this is true for most outcome domains, and for feasibility, specific outcomes are necessarily combined. Health professionals also considered that expectations about an outcome may differ based on the quality of transplantation (eg, from a living donor and a deceased extended criteria donor), which needed to be considered in establishing a core outcome domain.
DISCUSSION
Stakeholders agreed that core outcome domains for kidney transplantation should include graft health, mortality, cardiovascular disease, infection, cancer, and patient-reported outcomes (ie, life participation) based on their direct relevance for decision-making. Graft survival was unequivocally the dominant priority for patients/caregivers and health professionals, a tangible outcome that offered quality of life gains compared to dialysis. Health professionals deliberated on the importance of graft function in terms of impact on the patients’ functioning and well-being, and validity in predicting graft loss. They also raised concerns about the potential misinterpretation and obscurities around the term and meaning of rejection. The discussions from the workshop showed that patients were focused on well-being and avoiding dialysis, and viewed death as inevitable. Preventing premature death was upheld as a core responsibility among health professionals, and for regulators was a necessary safety consideration.
In the Delphi survey, no patient-reported outcome met the criteria for inclusion as a core outcome domain.34 In these consensus workshops, all stakeholder groups advocated for patient-reported outcomes driven by patient priorities and goals, and capturing symptom burden. Patients emphasized that kidney transplantation could enable them to do activities that provided them with a sense of self-value, purpose, fulfilment and enjoyment, and the narrower conceptualization of “ability to work” is not pertinent to all patients (students or retirees). The ability to participate in meaningful activities may be an appropriate patient-reported outcome domain, as it should be relevant to all ages and social systems. Health professionals noted that patient-reported outcomes were increasingly required by regulatory and funding agencies. Similarly, in a recent Outcome Measures in Rheumatology meeting, participants suggested that patients should be involved as partners during all stages in developing core outcomes measures, and highlighted the importance of validating measures across countries, cultures, and languages.43
Some health professionals challenged outcomes that may not be regarded as “transplant-specific” and raised concerns about the feasibility of including long-term outcomes and outcomes that would not be responsive to specific interventions. Indeed, few trials are beyond 1 year in duration.15 However, novel trial designs such as pragmatic trials conducted in clinical settings, and registry-based trials that capitalize on recruitment and follow up structures of registries, are gaining traction, and may overcome these concerns.44-51 Importantly, it should be acknowledged that triallists and other stakeholders may have different perspectives (eg, to evaluate the effectiveness of an intervention) and considerations about what outcomes to select for trials (eg, based on feasibility, responsiveness, regulatory requirements, cost-efficiency, and ensuring quality and safety). These workshops provided further clarification about the context and implementation of core outcomes. In the context of decision making, patients and clinicians want to whether the intervention affects the outcomes they regard as important. As such, core outcomes should reflect the shared priorities of patients and health professionals and be reported in all trials (in kidney transplantation), regardless of the expected effect of an intervention.
The recommendations arising from this workshop (Table 2) will be taken forward in establishing core outcome domains to be reported in trials conducted in kidney transplant recipients. After this, we will identify the core outcome measure for each of these outcome domains. This should facilitate better understanding, acceptance and uptake of core outcome domains so clinical trials report outcomes that are important to patients and clinicians, and inform shared-decisions about treatment in kidney transplantation.
ACKNOWLEDGMENTS
The authors thank The Transplantation Society for providing the venue for the SONG-Tx Hong Kong Workshop during the 26th International Congress of The Transplantation Society.
We acknowledge, with permission, all the attendees listed below who attended the consensus workshops.
SONG-Tx Boston 2016 Consensus workshop: Ajay Israni, Alan Leichtman, Allan Massie, Allison Tong, Allyson Hart, Angelique Ralph, Beatrice Oakley, Benedicte Sautenet, Bert Kasiske, Camilla Hanson, Caren Rose, Chris Watson, Christine Murphy, Christophe Legendre, Dana Basken, David Rosenbloom, David Shakespeare, Devin Peipert, Fritz Diekmann, Gabriel Danovitch, Germaine Wong, Gerry Chipman, Greg Knoll, Hallvard Holdaas, Heidi Basken, Ina Jochmans, Jamie Wells, Jayme Locke, Jennifer Trofe-Clark, Jenny Shen, Jeremy Chapman, Jessica Ryan, John Gill, John Kanellis, John Scandling, Joseph Kacoyannakis, Kjersti Lonning, Klemens Budde, Klemens Meyer, Krista Lentine, Linda Rosenbloom, Ling-Xin Chen, Lorelei Basken, Lorna Marson, Marc Cavaillé-Coll, Matthias Buchler, Michael Germain, Michael Murphy, Nicole Evangelidis, Peter Friend, Peter Reese, Phil Clayton, Phil O’Connell, Rainer Oberbauer, Randall Morris, Robert Bulger, Robert Steiner, Rosemary Kacoyannakis, Roslyn Mannon, Sabina De Geest, Sheila Jowsey-Gregoire, Siah Kim, Sobhana Thangaraju, Stephen Fader, Steve Alexander.
SONG-Tx Hong Kong 2016 Consensus workshop: Beatriz Dominguez-Gil, Benedicte Sautenet, Benita Padilla, Brian Chu Yuen Tse, Camilla Hanson, Chi Yan Yuen, Choi Fong Hau, Curie Ahn, Deneb Cheung, Dirk Kuypers, Fabian Halleck, Frank Dor, Germaine Wong, Greg Knoll, Hai An Ha Phan, Janet Hui, Jeremy Chapman, Jif Wong, Joen Hui, Jonathan Craig, John Gill, Hatem Amer, Helen Pilmore, Jayme Locke, Jongwon Ha, Kai Ming Chow, Klemens Budde, Kirsten Howard, Lalitha Raghuram, Lin Ping, Lionel Rostaing, Marina Ng, Madeleine Didsbury, Maggie Ma, Martin Howell, Mirjam Tielen, Nga Lun Mok, Nick Larkins, Paul Harden, Penny Allen, Peter Stock, Peter Nickerson, Richard Allen, Romina Danguilan, Ron Shapiro, Samuel Fung, Shigeru Satoh, Stephen McDonald, Tahir Aziz, Teck Chuan Voo, Terence Kee, Vasant Sumethkul, Vathsala Anantharaman, Vivekanand Jha, Allison Tong.
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Transplantation101(8):1887-1896, August 2017.
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