Over the past 50 years, remarkable progress has been made in kidney transplantation, largely owing to treatment advances and the growing number of trials in this area.1 Substantial reductions in rates of acute rejection have seen commensurate improvements in 1-year graft survival.2,3 However, kidney transplant recipients depend on lifelong immunosuppressive therapy, which is associated with increased risks of life-threatening comorbidities including cardiovascular disease, diabetes, and cancer. An estimated 50% of patients have died with a functioning graft 10 years after transplantation, mostly due to the consequences of over immunosuppression.4,5 Although transplant may improve patient quality of life compared with dialysis, immunosuppression-related side effects can diminish these potential benefits.6 Such challenges draw attention to the need for evidence-informed shared decision making based on trials that consistently report outcomes that are meaningful to both patients and clinicians.7
Trials in kidney transplantation are often short-term, and important outcomes, such as mortality, graft loss, and kidney function, are inconsistently and incompletely reported in randomized trials in kidney transplantation; with just one third reporting all 3 outcomes.8 Only 58% of trials report infection and 48% of trials report cancer.9 Less than 2% of trials of maintenance immunosuppression interventions report quality of life outcomes, with nearly all favoring the intervention.10 The heterogeneity of outcomes, many of which may not be directly relevant to patients, and selective reporting of outcomes diminishes the reliability and relevance of clinical trials for decision making.11
These problems are well recognized across many areas in healthcare, which has driven the development of core outcome sets, defined as an “agreed minimum set of outcomes to be reported in all trials” addressing a specific condition.12 The Standardized Outcomes in Nephrology (SONG) initiative was launched in 2014 to establish core outcomes across all stages of chronic kidney disease including kidney transplantation (SONG-Tx).13 As part of the SONG-Tx initiative, this study aimed to gain consensus among patients, caregivers and health professionals on critically important outcomes for trials in kidney transplantation. A core outcome set can improve the reporting of outcomes in trials permitting reliable comparisons of the effect of interventions across trials, and enhancing the usability and uptake of trial evidence in decision making.
MATERIALS AND METHODS
The Delphi technique is a validated approach for establishing consensus on core outcomes14-18 and consists of iterative surveys with anonymous responses to gain consensus among an “expert” panel19,20 (Figure S1, SDC,https://links.lww.com/TP/B436).
Participant Selection and Recruitment
Adult patients/caregivers (aged 18 years or older) and health professionals with an interest or experience in kidney transplantation were eligible to participate. Patients/caregivers included kidney transplant recipients, patients with chronic kidney disease stages 1 to 5, or on dialysis, their caregivers, family members, and living kidney donors. Health professionals included physicians (nephrologists, surgeons, and psychiatrists), nurses, allied health professionals (psychologists, social workers, dieticians, and pharmacists), policy makers/regulators, researchers, and industry.
To be broadly inclusive, we used multiple recruitment strategies. Patients/caregivers were recruited by site investigators at participating hospitals, patient organizations worldwide (Table S1, SDC,https://links.lww.com/TP/B436) using standardized invitation fliers, the SONG Network database by email, and via snowball sampling which included the use of social media. Health professionals were recruited through professional organizations (Table S1, SDC,https://links.lww.com/TP/B436) via a standard invitation email to their membership list, investigator networks, and the SONG database. The invitation directed participants to register their email on the SONG website to receive an email invitation with the unique survey link. The University of Sydney (2015-228), Baylor College of Medicine (H-37406), University of Calgary (REB15-1875), Salford Royal NHS Trust (13082B) and Sydney West Area Health Services (HREC2009/6/4.15) provided ethics approval.
Selection of Outcome Domains
We identified the outcome domains from a systematic review of outcomes reported in trials in kidney transplant recipients, studies on kidney transplant recipient preferences for outcomes,21 and studies focusing on patient-reported outcomes.10,22 The list of outcomes was reviewed by the investigators, and piloted among 8 patients. We programmed and administered the survey online using LimeSurvey from February to June 2016.23 The survey was conducted in English.
Round 1 included 35 outcome domains (Table S2, SDC,https://links.lww.com/TP/B436). Participants rated the importance of each outcome domain on a 9-point Likert scale using the GRADE scale (rating 1 to 3 indicated “limited importance,” 4 to 6 “important, but not critical,” and 7 to 9 “critical importance”).24 Free text boxes were provided for comments and participants could suggest new outcomes. Outcomes with a mean and median of more than or equal to 7 were taken through to round 2. New outcomes suggested by more than 10% of the participants would be included in the next round.
Participants rerated each outcome and provided (optional) comments. Participants reviewed their own score from round 1, and the distribution of the group responses on a column graph displayed by patients/caregivers, health professionals, and the weighted score of both groups combined. Participants were shown the comments from patients/caregivers and health professionals. If outcomes had a mean and median score of more than 7, and more than 50% of participants rated the outcome as 7 to 9, we retained those outcomes for round 3.
Participants were provided with their own score, the group responses and comments as per round 2 and asked to rerate the final set of outcomes. To assess the relative importance of outcomes, participants also completed a forced ranking exercise and ordered outcomes in order of importance using a drag-and-drop function.25
We assessed the mean, median, and the proportion of participants who rated 7 to 9 for each outcome across all rounds, and separated by patients/caregivers and health professionals. We compared the mean difference in rating scores between both stakeholder groups with a Wilcoxon signed rank test or a t test, significance at P less than 0.05. We performed subgroup analysis by country and age. For the forced ranking scores, we calculated the median and interquartile range (IQR) to determine the rank of each outcome. Statistical analyses were undertaken using R version 3.2.3 (R Foundation for Statistical Computing, Vienna, Austria).
Definition of Consensus for Core Outcomes
An a priori definition of consensus was not possible because of the unknown distribution of scores for the outcome domains. For feasibility, we aimed to identify the top 3 to 5 outcome domains indicated as critically important by both stakeholder groups. “Consensus” for a critical outcome domain was based on both stakeholder groups having a median score of greater than or equal to 8, a mean score greater than or equal to 7.5, the proportion of participants rating the outcome as ‘critically important’ being greater than or equal to 75%, and a median score of less than 10 in the forced ranking question.
We imported the comments into HyperRESEARCH (Version 3.7, Randolph, MA) software for qualitative data analysis. Using thematic analysis, KEM coded the text and inductively identified themes focusing on reasons for ratings, changes in ratings across rounds, and differences between stakeholder groups. Two investigators (B.S. and A.T.) who read the qualitative data, reviewed the preliminary analysis to ensure that the themes captured the range and depth of data.
In round 1, 1018 people from 79 countries participated, of whom 461 (45%) were patients/caregivers and 557 (55%) were health professionals. Round 2 was completed by 844 (83% response rate) participants from 70 countries, of whom 387 (46%) were patients/caregivers and 457 (54%) were health professionals. Round 3 was completed by 779 (77% response rate) participants with 360 (46%) patients/caregivers and 419 (54%) health professionals from 68 countries. Overall, the participant characteristics were consistent from rounds 1 to 3 (Tables 1 and 2).
Of the 360 patients/caregivers who completed all 3 rounds, 251 (69%) were kidney transplant recipients, 32 (9%) patients on dialysis, 17 (5%) patients not on any kidney replacement therapy, 35 (10%) living kidney donors, and 27 (7%) were caregivers/family members. The patients/caregivers were from 21 countries. Of the 419 health professionals, 281 (59%) were nephrologists, 61 (13%) researchers, and 49 (10%) nurses. Health professionals were from 64 countries.
Ratings and Ranking
The mean and median scores for each of the 35 outcome domains and proportion of participants scoring outcomes as 7 to 9 (critical importance) for each outcome are included in Table S3, SDC (https://links.lww.com/TP/B436). For patients/caregivers, the 4 outcomes with the highest mean scores were: graft loss (8.3; SD, 1.3), graft function (8.1; SD, 1.3), chronic graft rejection (7.9; SD, 1.5), and acute graft rejection (7.9; SD, 1.6). For health professionals, the 4 top outcomes were graft loss (8.4; SD, 1.8), mortality (8.3; SD, 2.3), graft function (7.9; SD, 1.7), and chronic graft rejection (7.8; SD, 1.6). Thirteen outcomes had a mean or median score of less than 7 among both groups and were excluded from round 2 (Table S3, SDC,https://links.lww.com/TP/B436). None of the new outcomes were suggested by more than 10% of the participants (Table S4, SDC,https://links.lww.com/TP/B436).
The mean and median scores for each of the 22 outcome domains and proportion of participants scoring the outcome as 7 to 9 (critical importance) for each outcome are included in Table S5, SDC (https://links.lww.com/TP/B436). For patients/caregivers, the 4 outcomes with the highest mean scores were: graft loss (8.6; SD, 0.8), chronic graft rejection (8.5; SD, 0.9), graft function (8.5; SD, 1.0), and acute graft rejection (8.2; SD, 1.2). For health professionals, the 4 highest were graft loss (8.8; SD, 1.5), mortality (8.7; SD, 1.1), graft function (8.4; SD, 1.0), and chronic graft rejection (8.3; SD, 0.9). Six outcomes were excluded from round 3 because they had a mean and median score of 7 or less with less than 50% of the participants rating the outcome 7 to 9 (Table S5, SDC, https://links.lww.com/TP/B436).
The mean and median score for each of the 16 outcome domains and the proportion of participants scoring the outcome as 7 to 9 (of critical importance) for each outcome are shown in Table S6 and Figure S2, SDC (https://links.lww.com/TP/B436). For patients/caregivers, the 4 outcomes with the highest mean scores were: graft loss (8.8; SD, 0.6), chronic graft rejection (8.6; SD, 0.8), graft function (8.6; SD, 0.9), and acute graft rejection (8.3; SD, 1.0). The mean scores by age group are shown in Table S7, SDC (https://links.lww.com/TP/B436). For health professionals, the 4 highest were graft loss (8.9; SD, 0.4), mortality (8.8; SD, 0.7), graft function (8.6; SD, 0.7), and chronic graft rejection (8.5; SD, 0.8). Median rank scores (shown in Figure S3, SDC,https://links.lww.com/TP/B436) and IQR were calculated from the forced ranking exercise. Based on the median rank scores and IQR, the 4 most important outcomes for patients/caregivers were graft loss (median score, 3; IQR, 2-5), chronic graft rejection (median score, 3; IQR, 2-5), acute graft rejection (median score, 4; IQR, 2-6), and graft function (median score, 5; IQR, 3-7). For health professionals, the 4 most important were graft loss (median score, 3; IQR, 2-3), mortality (median score, 3; IQR, 1-4), graft function (median score, 5; IQR, 3-6), chronic graft rejection (median score, 5; IQR, 3-6).
Eight of the 16 outcomes in round 3 met all 4 consensus criteria (mean rating, ≥ 7.5; median rating, ≥ 8; proportion of 7 to 9 rating scores, ≥ 75%; median rank score, < 10) in both stakeholder groups. These were: graft function, mortality, acute graft rejection, chronic graft rejection, graft loss, infection, cardiovascular disease and cancer (nonskin). Figure 1 depicts all 16 outcomes from round 3 against the 4 consensus criteria.
Changes in Scores From Rounds 1 to 3
The 8 outcomes that fulfilled the consensus criteria were the same across the 3 rounds for both stakeholder groups. For patients/caregivers, the mean rating scores for 15 of the 16 outcomes in round 3 increased and only the score for blood pressure decreased. For health professionals, the mean scores for 14 of the 16 outcomes in Round 3 increased. The results are presented in Figures 2 and 3.
Differences Between Stakeholder Groups
The mean differences in ratings between both stakeholder groups across all rounds are shown in Figure 4. Patients/caregivers rated 11 outcome domains higher than health professionals: skin cancer (mean difference 1.0, P < 0.001), surgical complications (0.7, P < 0.001), cognition (0.6, P < 0.001), blood pressure (0.6, P < 0.001), depression (0.5, P < 0.001), ability to work (0.5, P < 0.001), acute graft rejection (0.3, P < 0.001), non-skin cancer (0.3, P < 0.001), infection (0.3, P < 0.001), diabetes (0.2, P < 0.001), and chronic graft rejection (0.1, P = 0.022). Two outcomes were rated higher by health professionals: mortality (0.4, P < 0.001) and hospitalization (0.2, P = 0.033). The subgroup analyses for countries with more than 10 participants for outcomes rated higher by patients/caregivers (ie, outcomes with a mean difference of 0.5 or more) are shown in Table S8, SDC (https://links.lww.com/TP/B436). There were no differences in the rating of these outcomes across countries except for cognition and depression.
Themes From Comments
We identified 5 themes that reflected the reasons, changes and differences in the rating of outcomes: capacity to control and inevitability, personal relevance, debilitating repercussions, understanding and gaining awareness of risks, and addressing critical knowledge gaps. The description of the themes in the following section applies to both stakeholder groups unless otherwise specified, and supporting quotations are provided in Table 3.
Capacity to Control and Inevitability
Although participants recognized some outcomes, such as blood pressure or skin cancer, as important, these were rated of relatively lower importance if perceived as preventable, treatable, or non–life-threatening. Across rounds, some participants decreased their ratings because they realized that certain outcomes could be feasibly improved—“I changed my answer. It's critical, but experienced surgeons make miracles happen.” For patients, some outcomes were considered of lower importance if they were inevitable—“death comes to us all, but maintaining quality of life while living is more important.”
Participants considered the importance of outcomes in terms of the patient/caregivers' life stage, health status, and personal experience, and this was maintained across rounds. For example, patients who were retired rated ability to work of lower importance. However, some recognized that fertility and ability to work would be an important outcome for younger people, and thus adjusted their rating to be “sympathetic” to other patients in different stages of life.
Outcomes seen as severely debilitating, distressing, or which would lead to serious comorbidities or hospitalization were rated of higher importance. For patients, graft loss meant a return to dialysis, which was described as “devastating” and “worse than the fear of death.” In contrast, some health professionals agreed that losing the graft was a “main hard endpoint,” but “relative to death, [it] cannot receive the highest rating.”
Understanding and Gaining Awareness of Risks
Patients/caregivers increased their ratings across rounds as read comments from health professionals and became “enlightened” about the risks of outcomes. Outcomes were rated higher if they learned that it was associated with a greater risk of graft loss and chronic graft rejection—“I'm naturally going to increase my rating if the pro[fessional]'s think it's critical.” Health professionals expressed appreciation and “respect” of the importance of outcomes to patients, namely psychosocial and disabling outcomes—“underestimated the importance based on patient feedback.”
Addressing Critical Knowledge Gaps
Participants recognized the unresolved challenges of preventing complications including rejection, graft function, cancer, infection, and diabetes, which prompted them to assign higher importance to these outcomes. Health professionals suggested that “long standing issues” that lacked evidence should also be high priorities for research and would benefit patients, for example, ability to work.
The outcomes of critical importance for patients/caregivers and health professionals were graft loss, graft function, acute graft rejection, chronic graft rejection, mortality, cardiovascular disease, infection, and cancer (non-skin). Overall, the results were congruent between the 2 stakeholder groups, with the same top 8 outcomes. Graft-related outcomes comprised the top 4 for both patients/caregivers and health professionals, consistent with research priority setting studies.26-28 For patients, returning to dialysis was a devastating consequence of graft failure that could even be worse than death. The critically important outcomes based on consensus echo the foremost challenges in transplantation, specifically, balancing graft survival and graft complications, with the risk of severe medical comorbidities.26,29-33 The other outcomes that remained in the final round of the Delphi survey were mostly clinical complications, of which skin cancer, diabetes, surgical complications, cognition, and depression were more important to patients/caregivers than they were to health professionals. Only 1 patient-reported outcome (ability to work) remained in round 3. This may reflect the gains in quality of life owing to kidney transplantation compared with dialysis, and that various dimensions of quality of life are implicit in graft outcomes and severe medical complications.
Although mortality was rated critically important for both stakeholder groups, the mean rating score was higher for health professionals (8.3) and ranked second after graft loss, compared with patients/caregivers (7.6) where mortality ranked fifth (below all the graft related outcomes). This discrepancy could be due to differences in how patients/caregivers and health professionals conceptualize death. Free text comments suggest that patients accept death as unavoidable, beyond their control, and therefore place greater importance on having a good quality of life. For health professionals, patient survival was entrenched as their primary goal of care and deemed to be the principal hard endpoint.34
Patients and caregivers placed greater importance on skin cancer, surgical complications, cognition, depression, blood pressure, and ability to work, compared with health professionals. The discrepancy in the prioritization of skin cancer may reflect geographical variations in the risk of skin cancer. We noted that patients/caregivers in countries with public campaigns for skin cancer prevention (United States, South Africa, Canada and Australia35-38), on average, rated skin cancer as critically important. Patients and caregivers expressed some fears about surgical complications, which may in part explain the higher rating. Although mental health and cognition outcomes improve after kidney transplantation, kidney transplant recipients are still at higher risk of cognitive impairment compared with the general population.33,39-41 This may also be attributable to the growing population of older recipients in whom cognitive decline is more prevalent.42 Such problems remain underrecognized and few studies have addressed the effect of transplantation on cognitive function.43,44 Blood pressure was initially rated highly, then decreased from round 1 to 3. From the comments, we speculate that patients became more aware that blood pressure was manageable after reading comments from health professionals. Ability to work was critically important to patients/caregivers across countries, some of whom regarded working as a key measure of transplant success and return to normality.
Unlike for hemodialysis, patient-reported outcomes were not prioritized as highly in kidney transplantation. In the Delphi survey on hemodialysis, ability to travel and dialysis-free time were rated markedly higher by patients/caregivers than providers.17 Also, a wider range of lifestyle patient-reported outcomes remained critically important in hemodialysis for both stakeholder groups (ability to travel, dialysis-free time, postdialysis fatigue, mobility, fatigue, social impact, pain, and ability to work). These differences between hemodialysis and kidney transplantation may be indicative of the considerable improvements in quality of life achieved through kidney transplant. The overriding goal for kidney transplant recipients was to protect their graft to maintain their quality of life and remain free from the constraints and distress of dialysis.45,46
The consensus between patients/caregivers and health professionals supports the inclusion of graft outcomes and medical comorbidities in a core outcome set for kidney transplantation. However, the, dominant focus on the clinical challenges of kidney transplantation may have led to patient-reported outcomes being assigned a lower rating score. For example, because quality of life is markedly improved by transplantation, compared to dialysis, it could be assumed as a given provided the graft continued to function. This is pertinent given the increasing emphasis on including patient-reported outcome measures in trials, to assess how patients feel and function.47 Moreover, patient-reported outcome measures are now required by regulators such as the US Food and Drug Administration to support claims for medical product labeling.48 Thus, we recommend to include a patient-reported outcome domain in the core set. Although “ability to work” was the highest rated patient-reported outcome domain in round 3, this may have lower personal relevance to, for example, patients who are studying or retired. Thus, further work is needed to refine this outcome domain such that it is more broadly relevant to all kidney transplant populations, irrespective of age, sex, and socioeconomic factors.
Compared with other Delphi surveys used to establish core outcomes, our sample size is large with a broad representation of different stakeholders across 79 countries and had a high response rate of 77% by round 3.45,46 Our findings also included qualitative data to provide further insights into the meaning, reasons and interpretations of the outcomes by participants. However, there are some potential limitations. For technical reasons and feasibility, we administered the survey in English language, which precluded a larger representation of patients and caregivers from non–English-speaking countries with different health systems. Therefore, the generalizability to non–English-speaking countries may be uncertain. Also, the survey could only be accessed online to facilitate broader dissemination and minimize data entry errors, which limited participation to those with internet access and computer literacy.
Core outcomes should be reported in all trials in kidney transplantation because they are relevant and important to patients and clinicians. Patients and clinicians want to know the effect of an intervention on outcomes they regard as critically important irrespective of whether the intervention makes a difference. Researchers are not required to use a core outcome as a primary endpoint to estimate the sample size required to adequately power a study. Also, researchers may add other outcomes based on other considerations including responsiveness to an intervention and feasibility.
Our international SONG-Tx Delphi survey has achieved clear consensus on high priority outcome domains to report in all trials involving kidney transplant recipients. These pertained to preservation of the graft and common life-threatening medical complications—cancer, infection, and cardiovascular disease. However, there is increasing emphasis on explicitly including patient-reported outcomes, which may be inherent in graft survival and clinical complications. Further stakeholder engagement through consensus workshops is needed to discuss the inclusion of patient-reported outcomes and to ascertain appropriate, feasible, and acceptable approaches for establishing core outcome domains in kidney transplantation. We will present the findings from the Delphi survey at SONG-Tx consensus workshops for review and discussion by patients, caregivers, clinicians, researchers, and policy makers. Once the core outcome domains are established, subsequent work to identify core outcome measures will ensue, which may be informed from complementary initiatives such as the Clinical Data Interchange Standards Consortium. Clinical Data Interchange Standards Consortium recently published the Kidney Transplant Therapeutic Area User Guide to facilitate standardized reporting of data.49
Improving the consistency and relevance of trial endpoints in kidney transplantation can ultimately empower patients and clinicians to make critical treatment decisions based on outcomes that explicitly matter to them.
The authors thank all the participants who participated on the SONG-Tx Delphi Panel. The authors are very grateful to all the collaborating organizations for help in inviting patients, caregivers, and health professionals to participate.
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