Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers, and health professionals.

BACKGROUND: Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in CKD, which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. METHODS: Online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals, who could read English, Spanish, or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a best-worst scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. RESULTS: In total, 1 399 participants from 73 countries completed Round 1 of the Delphi survey including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization, and cardiovascular disease (mean difference > 0.3). Consensus was based upon the two groups yielding median scores of ≥ 7 and mean scores > 7, and the proportions of both groups rating the outcome as 'critically important' being greater than 50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. CONCLUSION: Across trials in CKD, the outcomes of highest priority to patients, caregivers, and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death.

Potential Mechanisms Involved in Chronic Kidney Disease of Unclear Etiology.

BACKGROUND AND OBJECTIVES: The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Migrants with Mesoamerican nephropathy kidney failure (n=52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes (n=63) and age/sex/place of origin-matched healthy participants (n=16). Survey results were extended to the bench; C57BL/6 mice (n=73) received 10-15 weekly intraperitoneal injections of paraquat (a reactive oxygen species-generating herbicide) or vehicle. Kidney function, histology, and expression of organic cation transporter-2 (proximal tubule entry for paraquat) and multidrug and toxin extrusion 1 (extrusion pathway) were examined. Kidney biopsies from Nicaraguan patients with acute Mesoamerican nephropathy were stained for the above transporters and compared with patients with tubulointerstitial nephritis and without Mesoamerican nephropathy. RESULTS: Patients with Mesoamerican nephropathy and kidney failure were young agricultural workers, almost exclusively men; the majority were from Mexico and El Salvador; and they had prior exposures to agrochemicals, including paraquat (27%). After adjustment for age/sex, exposure to any agrochemical or paraquat was associated with Mesoamerican nephropathy kidney failure (odds ratio, 4.86; 95% confidence interval, 1.82 to 12.96; P=0.002 and odds ratio, 12.25; 95% confidence interval, 1.51 to 99.36; P=0.02, respectively). Adjusted for age/sex and other covariates, 1 year of agrochemical exposure was associated with Mesoamerican nephropathy kidney failure (odds ratio, 1.23; 95% confidence interval, 1.04 to 1.44; P=0.02). Compared with 16 matched healthy controls, Mesoamerican nephropathy kidney failure was significantly associated with exposure to paraquat and agrochemicals. Paraquat-treated male mice developed kidney failure and tubulointerstitial nephritis consistent with Mesoamerican nephropathy. Organic cation transporter-2 expression was higher in male kidneys versus female kidneys. Paraquat treatment increased organic cation transporter-2 expression and decreased multidrug and toxin extrusion 1 expression in male kidneys; similar results were observed in the kidneys of Nicaraguan patients with Mesoamerican nephropathy. CONCLUSIONS: Exposure to agrochemicals is associated with Mesoamerican nephropathy, and chronic exposure of mice to paraquat, a prototypical oxidant, induced kidney failure similar to Mesoamerican nephropathy.

Establishing a core outcome measure for life participation in patients receiving peritoneal dialysis: A Standardised Outcomes in Nephrology-Peritoneal Dialysis consensus workshop report.

BACKGROUND: Life participation is an outcome of critical importance to patients receiving peritoneal dialysis (PD). However, there is no widely accepted or validated tool for measuring life participation in patients receiving PD. METHODS: Online consensus workshop to identify the essential characteristics of life participation as a core outcome, with the goal of establishing a patient-reported outcome measure for use in all trials in patients receiving PD. Thematic analysis of transcripts was performed. RESULTS: Fifty-six participants, including 17 patients and caregivers, from 15 countries convened via online videoconference. Four themes were identified: reconfiguring expectations of daily living (accepting day-to-day fluctuation as the norm, shifting thresholds of acceptability, preserving gains in flexibility and freedom), ensuring broad applicability and interpretability (establishing cross-cultural relevance, incorporating valued activities, distinguishing unmodifiable barriers to life participation), capturing transitions between modalities and how they affect life participation (responsive to trajectory towards stable, reflecting changes with dialysis transitions) and maximising feasibility of implementation (reducing completion burden, administrable with ease and flexibility). CONCLUSIONS: There is a need for a validated, generalisable outcome measure for life participation in patients receiving PD. Feasibility, including length of time to complete and flexible mode of delivery, are important to allow implementation in all trials that include patients receiving PD.

A Core Outcome Set for Trials in Glomerular Disease: A Report of the Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) Stakeholder Workshops.

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.

Standardised Outcomes in Nephrology - Chronic Kidney Disease (SONG-CKD): a protocol for establishing a core outcome set for adults with chronic kidney disease who do not require kidney replacement therapy.

BACKGROUND: Globally, over 1.2 million people die from chronic kidney disease (CKD) every year. Patients with CKD are up to 10 times more likely to die prematurely than progress to kidney failure requiring kidney replacement therapy. The burden of symptoms and impaired quality of life in CKD may be compounded by comorbidities and treatment side effects. However, patient-important outcomes remain inconsistently and infrequently reported in trials in patients with CKD, which can limit evidence-informed decision-making. The Standardised Outcomes in Nephrology - Chronic Kidney Disease (SONG-CKD) aims to establish a consensus-based core outcome set for trials in patients with CKD not yet requiring kidney replacement therapy to ensure outcomes of relevance to patients, caregivers and health professionals are consistently reported in trials. METHODS: SONG-CKD involves four phases: a systematic review to identify outcomes (domains and measures) that have been reported in randomised controlled trials involving adults with CKD who do not require kidney replacement therapy; stakeholder key informant interviews with health professionals involved in the care of adults with CKD to ascertain their views on establishing core outcomes in CKD; an international two-round online Delphi survey with patients, caregivers, clinicians, researchers, policy makers and industry representatives to obtain consensus on critically important outcome domains; and stakeholder consensus workshops to review and finalise the set of core outcome domains for trials in CKD. DISCUSSION: Establishing a core outcome set to be reported in trials in patients with CKD will enhance the relevance, transparency and impact of research to improve the lives of people with CKD. TRIAL REGISTRATION: Not applicable. This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database: http://www.comet-initiative.org/Studies/Details/1653 .

Dose of Continuous Renal Replacement Therapy in Critically Ill Patients: A Bona Fide Quality Indicator.

Acute kidney injury (AKI) is common in critically ill patients, and renal replacement therapy (RRT) constitutes an important aspect of acute management during critical illness. Continuous RRT (CRRT) is frequently utilized in intensive care unit settings, particularly in patients with severe AKI, fluid overload, and hemodynamic instability. The main goal of CRRT is to timely optimize solute control, acid-base, and volume status. Total effluent dose of CRRT is a deliverable that depends on multiple factors and therefore should be systematically monitored (prescribed vs. delivered) and iteratively adjusted in a sustainable mode. In this manuscript, we review current evidence of CRRT dosing and provide recommendations for its implementation as a quality indicator of CRRT delivery.

Validation of a Core Patient-Reported Outcome Measure for Fatigue in Patients Receiving Hemodialysis: The SONG-HD Fatigue Instrument.

BACKGROUND AND OBJECTIVES: Fatigue is a very common and debilitating symptom and identified by patients as a critically important core outcome to be included in all trials involving patients receiving hemodialysis. A valid, standardized measure for fatigue is needed to yield meaningful and relevant evidence about this outcome. This study validated a core patient-reported outcome measure for fatigue in hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A longitudinal cohort study was conducted to assess the validity and reliability of a new fatigue measure (Standardized Outcomes in Nephrology-Hemodialysis Fatigue [SONG-HD Fatigue]). Eligible and consenting patients completed the measure at three time points: baseline, a week later, and 12 days following the second time point. Cronbach α and intraclass correlation coefficient were calculated to assess internal consistency, and Spearman rho was used to assess convergent validity. Confirmatory factor analysis was also conducted. Hemodialysis units in the United Kingdom, Australia, and Romania participated in this study. Adult patients aged 18 years and over who were English speaking and receiving maintenance hemodialysis were eligible to participate. Standardized Outcomes in Nephrology-Hemodialysis, the Visual Analog Scale for fatigue, the 12-Item Short Form Survey, and Functional Assessment of Chronic Illness Therapy-Fatigue were used. RESULTS: In total, 485 participants completed the study across the United Kingdom, Australia, and Romania. Psychometric assessment demonstrated that Standardized Outcomes in Nephrology-Hemodialysis is internally consistent (Cronbach α =0.81-0.86) and stable over a 1-week period (intraclass correlation coefficient =0.68-0.74). The measure demonstrated convergence with Functional Assessment of Chronic Illness Therapy-Fatigue and had moderate correlations with other measures that assessed related but not the same concept (the 12-Item Short Form Survey and the Visual Analog Scale). Confirmatory factor analysis supported the one-factor model. CONCLUSIONS: SONG-HD Fatigue seems to be a reliable and valid measure to be used in trials involving patients receiving hemodialysis.

Pre-ESKD Nephrology Care and Employment at the Start of Dialysis.

INTRODUCTION: Employment is associated with an improved sense of well-being and quality of life in patients with kidney disease. Earlier nephrology referral and longer duration of pre-end-stage kidney disease (ESKD) nephrology care are associated with improved health outcomes in patients with advanced kidney disease who initiate dialysis. It is unknown if pre-ESKD nephrology care helps patients stay employed leading up to dialysis initiation. METHODS: We used the US ESKD registry to identify adults aged 18-54 years who initiated dialysis between 2007 and 2014. Analyses were restricted to patients who reported being employed 6 months prior to ESKD. We used multivariable regression models with estimated average marginal effects to examine the independent association between ≥6 months of pre-ESKD nephrology care and employment at dialysis initiation. To reduce bias, we conducted an instrumental variable (IV) analysis based on geographic variation in pre-ESKD care. RESULTS: Of 75,700 patients included in study cohort, 49% reported receiving pre-ESKD nephrology care for ≥6 months, and 62% were employed at dialysis initiation. Although geographic variation in pre-ESKD nephrology care was strongly associated with the likelihood that working-aged patients in our analytic cohort received pre-ESKD care, the receipt of pre-ESKD nephrology care was not significantly associated with employment at dialysis initiation; estimated probability: 5%; 95% confidence interval (CI) -6% to 14%. CONCLUSIONS: Pre-ESKD nephrology care 6 months prior to initiation of dialysis is not associated with the likelihood of remaining employed at the initiation of dialysis. Although nephrology care has potential to help patients remain employed, this benefit is not manifested in current practice.

Patient and Caregiver Priorities for Outcomes in CKD: A Multinational Nominal Group Technique Study.

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD) are at an increased risk for premature death, cardiovascular disease, and burdensome symptoms that impair quality of life. We aimed to identify patient and caregiver priorities for outcomes in CKD. STUDY DESIGN: Focus groups with nominal group technique. SETTING & PARTICIPANTS: Adult patients with CKD (all stages) and caregivers in the United States, Australia, and United Kingdom. ANALYTICAL APPROACH: Participants identified, ranked, and discussed outcomes that were important during the stages of CKD before kidney replacement therapy. For each outcome, we calculated a mean importance score (scale, 0-1). Qualitative data were analyzed using thematic analysis. RESULTS: 67 (54 patients, 13 caregivers) participated in 10 groups and identified 36 outcomes. The 5 top-ranked outcomes for patients were kidney function (importance score, 0.42), end-stage kidney disease (0.29), fatigue (0.26), mortality (0.25), and life participation (0.20); and for caregivers, the top 5 outcomes were life participation (importance score, 0.38), kidney function (0.37), mortality (0.23), fatigue (0.21), and anxiety (0.20). Blood pressure, cognition, and depression were consistently ranked in the top 10 outcomes across role (patient/caregiver), country, and treatment stage. Five themes were identified: re-evaluating and reframing life, intensified kidney consciousness, battling unrelenting and debilitating burdens, dreading upheaval and constraints, and taboo and unspoken concerns. LIMITATIONS: Only English-speaking participants were included. CONCLUSIONS: Patients and caregivers gave highest priority to kidney function, mortality, fatigue, life participation, anxiety, and depression. Consistent reporting of these outcomes in research may inform shared decision making based on patient and caregiver priorities in CKD.

Patient and Caregiver Perspectives on Terms Used to Describe Kidney Health.

BACKGROUND AND OBJECTIVES: The language used to communicate important aspects of kidney health is inconsistent and may be conceptualized differently by patients and health professionals. These problems may impair the quality of communication, care, and patient outcomes. We aimed to describe the perspectives of patients on terms used to describe kidney health. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD (n=54) and caregivers (n=13) from the United States, United Kingdom, and Australia participated in ten focus groups to discuss terms for kidney health (including kidney, renal, CKD, ESKD, kidney failure, and descriptors for kidney function). We analyzed the data using thematic analysis. RESULTS: We identified four themes: provoking and exacerbating undue trauma (fear of the unknown, denoting impending death, despair in having incurable or untreatable disease, premature labeling and assumptions, judgment, stigma, and failure of self); frustrated by ambiguity (confused by medicalized language, lacking personal relevance, baffled by imprecision in meaning, and/or opposed to obsolete terms); making sense of the prognostic enigma (conceptualizing level of kidney function, correlating with symptoms and effect on life, predicting progression, and need for intervention); and mobilizing self-management (confronting reality, enabling planning and preparation, taking ownership for change, learning medical terms for self-advocacy, and educating others). CONCLUSIONS: The obscurity and imprecision of terms in CKD can be unduly distressing and traumatizing for patients, which can impair decision making and self-management. Consistent and meaningful patient-centered terminology may improve patient autonomy, satisfaction, and outcomes.

A historical perspective of how public policy shaped dialysis care delivery in the United States.

Broadly defined public policy has been said to be whatever "governments choose to do or not to do" As applied to healthcare, public policy can be traced back to the 4000-year-old Code of Hammurabi. As it applies to dialysis care its history is barely 50 years old since national coverage for end-stage renal disease (ESRD) was legislated as Public Law 92-603 in 1972. As with most healthcare policy changes, it was a result of medical progress which had changed renal function replacement by dialysis from its rudimentary beginnings during the Second World War into an experimental acute life-saving procedure in the 1950s and to an established life-sustaining treatment for the otherwise fatal disease of uremia in the 1960s that was limited by its costs. Since 1973, the Medicare ESRD Program has saved the lives of thousands of individuals, a compassionate achievement that has come at increasing costs which have exceeded all estimates and evaded containment. Apart from cost containment, policy changes in dialysis care have been directed at improving its safety and adequacy. Some of the results of these changes are evident as one compares the outcomes and complications of dialysis encountered in the 1970s to those in the present; others, particularly those related to vascular access and hospitalization rates have improved modestly. This article recounts the historical background in which national coverage for dialysis care was developed, legislated and has evolved over the past 50 years.

Physician reimbursement for outpatient dialysis care: Past, present, and future.

Ever since Medicare began covering nearly every patient with end-stage renal disease in the United States, reimbursement for dialysis services has deviated from traditional fee-for-service. The method of reimbursing physicians for outpatient dialysis care has undergone a series of reforms in an effort to improve the overall quality of dialysis care and to control healthcare costs-changes that we are still seeing today. In 2004, the Centers for Medicare and Medicaid Services (CMS) changed the Monthly Capitation Payment (MCP) for physician reimbursement to the tiered fee-for-service system that is used today. This most recent reform encouraged more frequent face-to-face visits to patients receiving dialysis. While the quantity of visits increased in response to the change in reimbursement, the quality of care did not meaningfully improve, the policy may have had unintended negative health consequences and may have led to increases in wasteful physician and advanced practitioner effort. There are several promising opportunities to reform economic incentives around physician dialysis care that could improve the quality and value of care. These include new pay-for-performance initiatives, implementing incentives for high-quality care within fully capitated payment models, and reforming the MCP itself to link payment to high-value dialysis services.

Predialysis Nephrology Care and Incident Atrial Fibrillation in Older Patients With ESKD Initiating Dialysis.

BACKGROUND: Atrial fibrillation (AF) is common in patients with end-stage kidney disease (ESKD) on dialysis. Whether pre-ESKD nephrology care associates with AF is uncertain. METHODS: We conducted a retrospective cohort study of older US patients (≥67 years) with Medicare A&B who initiated dialysis (1996-2013) without a prior diagnosis of AF. Patients were categorized by the duration and number of predialysis nephrology outpatient visits. Patients were followed for 1 year for a new diagnosis of AF. We used multivariable Cox proportional hazards regression while accounting for the competing risks of kidney transplantation and death. RESULTS: We identified 316,067 patients with ESKD initiating dialysis between 1996 and 2013 who had no prior AF diagnosis. In this cohort, 66.9% had any pre-ESKD outpatient nephrology care, with the first outpatient nephrology visit before dialysis initiation occurring at ≤6 months in 17.9%, 7 to 12 months in 9.4%, and >12 months in 39.6%. Outpatient pre-ESKD nephrology care for ≤6, 7 to 12, and >12 months versus none yielded adjusted cause-specific hazard ratios (HRs) of 0.87 (95% CI: 0.84-0.89), 0.83 (95% CI: 0.81-0.86), and 0.85 (95% CI: 0.83-0.87) for incident AF, respectively. Further, having 1 to 4 pre-ESKD outpatient nephrology visits, 5 to 9 visits, and ≥10 visits versus none yielded adjusted cause-specific HRs of 0.89 (95% CI: 0.86-0.91), 0.86 (95% CI: 0.83-0.88), and 0.81 (95% CI: 0.79-0.83), respectively. CONCLUSIONS: Having any predialysis nephrology care before initiation of dialysis was associated with slightly lower adjusted rates of incident AF over the first year of dialysis. The optimal timing and intensity of nephrology care to reduce the incidence of AF and other adverse health events requires further study.