Implementing core outcomes in kidney disease: report of the Standardized Outcomes in Nephrology (SONG) implementation workshop.

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). Approach and Results We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(11.3%), as well as potentially druggable mutations (e.g.,HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.Peer reviewe

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; PPeer reviewe

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe

Defining Priorities for Future Research:Results of the UK Kidney Transplant Priority Setting Partnership

It has been suggested that the research priorities of those funding and performing research in transplantation may differ from those of end service users such as patients, carers and healthcare professionals involved in day-to-day care. The Kidney Transplant Priority Setting Partnership (PSP) was established with the aim of involving all stakeholders in prioritising future research in the field.The PSP methodology is as outlined by the James Lind Alliance. An initial survey collected unanswered research questions from patients, carers and clinicians. Duplicate and out-of-scope topics were excluded and the existing literature searched to identify topics answered by current evidence. An interim prioritisation survey asked patients and professionals to score the importance of the remaining questions to create a ranked long-list. These were considered at a final consensus workshop using a modified nominal group technique to agree a final top ten.The initial survey identified 497 questions from 183 respondents, covering all aspects of transplantation from assessment through to long-term follow-up. These were grouped into 90 unanswered "indicative" questions. The interim prioritisation survey received 256 responses (34.8% patients/carers, 10.9% donors and 54.3% professionals), resulting in a ranked list of 25 questions that were considered during the final workshop. Participants agreed a top ten priorities for future research that included optimisation of immunosuppression (improved monitoring, choice of regimen, personalisation), prevention of sensitisation and transplanting the sensitised patient, management of antibody-mediated rejection, long-term risks to live donors, methods of organ preservation, induction of tolerance and bioengineering of organs. There was evidence that patient and carer involvement had a significant impact on shaping the final priorities.The final list of priorities relates to all stages of the transplant process, including access to transplantation, living donation, organ preservation, post-transplant care and management of the failing transplant. This list of priorities will provide an invaluable resource for researchers and funders to direct future activity