Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease: A Systematic Review and Retrospective Individual Participant–Level Meta-analysis of Clinical Trials: Annals of Internal Medicine: Vol 177, No 7

Background: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. Purpose: To examine the association of ACEi or ARB treatment initiation, relative to a non–ACEi or ARB comparator, with rates of KFRT and death. Data Sources: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. Study Selection: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Data Extraction: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin–creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. Data Synthesis: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). Limitation: Individual participant–level data for hyperkalemia or acute kidney injury were not available. Conclusion: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42022307589)

Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria: A Cohort Study: Annals of Internal Medicine: Vol 177, No 4

Background: Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. Objective: To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). Design: Multicenter prospective cohort study. Setting: 7 U.S. clinical centers. Participants: 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin–creatinine ratio (UACR) less than 30 mg/g. Measurements: Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. Results: Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. Limitation: UACR was measured once. Conclusion: Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. Primary Funding Source: None.

Diagnostic Discordance, Uncertainty, and Treatment Ambiguity in Community-Acquired Pneumonia: A National Cohort Study of 115 U.S. Veterans Affairs Hospitals: Annals of Internal Medicine: Vol 177, No 9

Background: Evidence-based practice in community-acquired pneumonia often assumes an accurate initial diagnosis. Objective: To examine the evolution of pneumonia diagnoses among patients hospitalized from the emergency department (ED). Design: Retrospective nationwide cohort. Setting: 115 U.S. Veterans Affairs medical centers. Patients: Aged 18 years or older and hospitalized from the ED between 1 January 2015 and 31 January 2022. Measurements: Discordances between initial pneumonia diagnosis, discharge diagnosis, and radiographic diagnosis identified by natural language processing of clinician text, diagnostic coding, and antimicrobial treatment. Expressions of uncertainty in clinical notes, patient illness severity, treatments, and outcomes were compared. Results: Among 2 383 899 hospitalizations, 13.3% received an initial or discharge diagnosis and treatment of pneumonia: 9.1% received an initial diagnosis and 10.0% received a discharge diagnosis. Discordances between initial and discharge occurred in 57%. Among patients discharged with a pneumonia diagnosis and positive initial chest image, 33% lacked an initial diagnosis. Among patients diagnosed initially, 36% lacked a discharge diagnosis and 21% lacked positive initial chest imaging. Uncertainty was frequently expressed in clinical notes (58% in ED; 48% at discharge); 27% received diuretics, 36% received corticosteroids, and 10% received antibiotics, corticosteroids, and diuretics within 24 hours. Patients with discordant diagnoses had greater uncertainty and received more additional treatments, but only patients lacking an initial pneumonia diagnosis had higher 30-day mortality than concordant patients (14.4% [95% CI, 14.1% to 14.7%] vs. 10.6% [CI, 10.4% to 10.7%]). Patients with diagnostic discordance were more likely to present to high-complexity facilities with high ED patient load and inpatient census. Limitation: Retrospective analysis; did not examine causal relationships. Conclusion: More than half of all patients hospitalized and treated for pneumonia had discordant diagnoses from initial presentation to discharge. Treatments for other diagnoses and expressions of uncertainty were common. These findings highlight the need to recognize diagnostic uncertainty and treatment ambiguity in research and practice of pneumonia-related care. Primary Funding Source: The Gordon and Betty Moore Foundation.

Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2022 Clinical Practice Guideline

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 clinical practice guideline on prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease (CKD) is an update of the 2018 guideline from KDIGO. Methods: The KDIGO Work Group (WG) updated the guideline, which included reviewing and grading new evidence that was identified and summarized. As in the previous guideline, the WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of recommendations and used expert judgment to develop recommendations. New evidence led to updating of recommendations in the chapters on treatment of hepatitis C virus (HCV) infection in patients with CKD (Chapter 2), management of HCV infection before and after kidney transplant (Chapter 4), and diagnosis and management of kidney disease associated with HCV infection (Chapter 5). Recommendations in chapters on detection and evaluation of hepatitis C in CKD (Chapter 1) and prevention of HCV transmission in hemodialysis units (Chapter 3) were not updated because of an absence of significant new evidence. Recommendations: The 2022 updated guideline includes 43 graded recommendations and 20 ungraded recommendations, 7 of which are new or modified on the basis of the most recent evidence and consensus among the WG members. The updated guidelines recommend expanding treatment of hepatitis C with sofosbuvir-based regimens to patients with CKD glomerular filtration rate categories G4 and G5, including those receiving dialysis; expanding the donor pool for kidney transplant recipients by accepting HCV-positive kidneys regardless of the recipient’s HCV status; and initiating direct-acting antiviral treatment of HCV-infected patients with clinical evidence of glomerulonephritis without requiring kidney biopsy. The update also addresses the use of immunosuppressive regimens in such patients.

Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 177, No 2

Background: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. Objective: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). Design: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. Data Sources: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. Target Population: Persons eligible for gene therapy. Time Horizon: Lifetime. Perspective: U.S. health care sector and societal. Intervention: Gene therapy versus common care. Outcome Measures: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. Results of Base-Case Analysis: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. Results of Sensitivity Analysis: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. Limitation: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. Conclusion: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. Primary Funding Source: National Heart, Lung, and Blood Institute.

Demonstration Project of Long-Acting Antiretroviral Therapy in a Diverse Population of People With HIV

Background: Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables. Objective: To examine LA-ART in a population of PWH that includes those with viremia. Design: Observational cohort study. Setting: Urban academic safety-net HIV clinic. Patients: Publicly insured adults living with HIV with and without viral suppression, high rates of unstable housing, mental illness, and substance use. Intervention: Demonstration project of long-acting injectable CAB–RPV. Measurements: Descriptive statistics summarizing cohort outcomes to date, based on pharmacy team logs and electronic medical record data. Results: Between June 2021 and November 2022, 133 PWH at the Ward 86 HIV Clinic were started on LA-ART, 76 of whom had virologic suppression while using oral ART and 57 of whom had viremia. The median age was 46 years (IQR, 25 to 68 years); 117 (88%) were cisgender men, 83 (62%) had non-White race, 56 (42%) were experiencing unstable housing or homelessness, and 45 (34%) had substance use. Among those with virologic suppression, 100% (95% CI, 94% to 100%) maintained suppression. Among PWH with viremia, at a median of 33 days, 54 of 57 had viral suppression, 1 showed the expected 2-log10 reduction in HIV RNA level, and 2 experienced early virologic failure. Overall, 97.5% (CI, 89.1% to 99.8%) were projected to achieve virologic suppression by a median of 33 weeks. The current virologic failure rate of 1.5% in the cohort is similar to that across registrational clinical trials at 48 weeks. Limitation: Single-site study. Conclusion: This project demonstrates the ability of LA-ART to achieve virologic suppression among PWH, including those with viremia and challenges to adherence. Further data on the ability of LA-ART to achieve viral suppression in people with barriers to adherence are needed. Primary Funding Source: National Institutes of Health, City and County of San Francisco, and Health Resources and Services Administration.

Pharmacologic Treatment Initiation Among Medicare Beneficiaries Hospitalized With Alcohol Use Disorder

Preventing Type 2 Diabetes With Vitamin D: Therapy Versus Supplementation

2022 Clinical Practice Guideline Update for Diabetes Management of Chronic Kidney Disease: An Important First Step, More Work to Do

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19: A Randomized Platform Trial: Annals of Internal Medicine: Vol 176, No 5

Background: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. Objective: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. Design: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424) Setting: 12 clinical sites in Brazil. Participants: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. Intervention: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. Measurements: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. Results: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. Limitation: Low event rate overall, consistent with contemporary trials in vaccinated populations. Conclusion: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. Primary Funding Source: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.