Rates of adverse clinical events in patients with chronic kidney disease: analysis of electronic health records from the UK clinical practice research datalink linked to hospital data.

BACKGROUND: Further understanding of adverse clinical event rates in patients with chronic kidney disease (CKD) is required for improved quality of care. This study described baseline characteristics, adverse clinical event rates, and mortality risk in patients with CKD, accounting for CKD stage and dialysis status. METHODS: This retrospective, noninterventional cohort study included data from adults (aged ≥ 18 years) with two consecutive estimated glomerular filtration rates of < 60 ml/min/1.73 m2, recorded ≥ 3 months apart, from the UK Clinical Practice Research Datalink of electronic health records obtained between January 1, 2004, and December 31, 2017. Select adverse clinical events, associated with CKD and difficult to quantify in randomized trials, were assessed; defined by Read codes and International Classification of Diseases, Tenth Revision codes. Clinical event rates were assessed by dialysis status (dialysis-dependent [DD], incident dialysis-dependent [IDD], or non-dialysis-dependent [NDD]), dialysis modality (hemodialysis [HD] or peritoneal dialysis [PD]), baseline NDD-CKD stage (3a-5), and observation period. RESULTS: Overall, 310,953 patients with CKD were included. Comorbidities were more common in patients receiving dialysis than in NDD-CKD, and increased with advancing CKD stage. Rates of adverse clinical events, particularly hyperkalemia and infection/sepsis, also increased with advancing CKD stage and were higher in patients on HD versus PD. Mortality risk during follow-up (1-5-year range) was lowest in patients with stage 3a NDD-CKD (2.0-18.5%) and highest in patients with IDD-CKD (26.3-58.4%). CONCLUSIONS: These findings highlight the need to monitor patients with CKD for comorbidities and complications, as well as signs or symptoms of clinical adverse events.

Incidence of Uncommon Clinical Events in USA Patients with Dialysis-Dependent and Nondialysis-Dependent Chronic Kidney Disease: Analysis of Electronic Health Records from TriNetX.

INTRODUCTION: Further understanding of adverse clinical events in patients with chronic kidney disease (CKD) is needed. This study aimed to describe characteristics of patients with nondialysis-dependent (NDD) and dialysis-dependent (DD) CKD and to assess incidence rates of uncommon adverse clinical events of interest in these patients. METHODS: This retrospective study used electronic medical record data from USA CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 between January 1, 2010, and December 31, 2018, obtained from the USA-based TriNetX database. NDD-CKD and DD-CKD were diagnosed and staged from ≥2 consecutive eGFR readings, recorded ≥90 days apart. Dialysis was identified using procedure codes for renal replacement therapy. Outcomes assessed were select uncommon adverse clinical events, defined by International Classification of Disease, 9th and 10th Revision codes. RESULTS: Incidence rates of adverse clinical events per 100 person-years (95% confidence interval) were generally higher in patients with DD-CKD versus NDD-CKD. Differences were particularly pronounced for hyperkalemia (26.9 [26.2-27.6] vs. 4.5 [4.5-4.6]), acidosis (15.1 [14.7-15.6] vs. 3.4 [3.4-3.4]), and sepsis (14.6 [14.2-15.1] vs. 3.3 [3.3-3.4]). Among DD-CKD patients, incidence rates of adverse events were particularly high during the first 3 months following dialysis initiation. Incidence of adverse clinical events generally increased with decreasing eGFR among patients with NDD-CKD and with hemoglobin <10 g/dL in both NDD- and DD-CKD patients. CONCLUSIONS: Our results help establish baseline rates of uncommon adverse clinical events and provide additional evidence of increased morbidity for patients with DD-CKD versus NDD-CKD.

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.