Martin J. Landray

Key Points: The kidney failure risk equation showed excellent discrimination for treated kidney failure outcome in patients with CKD. In a wide range of causes of CKD, urine tubular biomarkers improved prediction of kidney disease progression beyond established clinical risk models. EGF, kidney injury molecule-1, and monocyte chemoattractant protein-1 added the most prognostic value. Background: Urine tubular biomarkers have previously been associated with chronic kidney disease (CKD) progression independently of eGFR and albuminuria. We evaluated whether nine urine tubular biomarkers could improve prediction of kidney failure beyond serum creatinine and urine albumin‑creatinine ratio among adults with CKD. Methods: Among 5100 participants in Study of Heart and Kidney Protection With Empagliflozin, a randomized trial that assessed the effects of empagliflozin 10 mg versus matching placebo among patients with CKD at risk of progression, nine urine creatinine-indexed tubular biomarkers were measured, including α ‐1 microglobulin, dickkopf-3, EGF, interleukin-18, kidney injury molecule‐1 (KIM‐1), monocyte chemoattractant protein‐1 (MCP‐1), neutrophil gelatinase-associated lipocalin, uromodulin, and human cartilage glycoprotein-40. Outcomes were kidney disease progression (treated kidney failure, renal death, or sustained ≥40% eGFR decline) and treated kidney failure (maintenance dialysis or kidney transplant). Relative to models based on the linear predictor of the kidney failure risk equation (KFRE), improvements in discrimination were estimated with further addition of the nine tubular biomarkers using absolute difference in Uno C-index. Results: Over a median 3.5 years of follow-up, 1191 participants experienced kidney disease progression and 461 experienced treated kidney failure. KFRE demonstrated excellent discrimination for treated kidney failure (C-index 0.858 [0.840–0.874]) and moderate discrimination for kidney disease progression (0.724 [0.705–0.743]). Addition of three biomarkers (MCP-1, KIM-1, and EGF) most strongly associated with CKD outcomes yielded some further improvement in predicting kidney failure (absolute difference 0.014 [0.009–0.024]) and kidney disease progression (0.038 [0.026–0.053]). Prediction of kidney outcomes was only slightly improved when further expanding from three to all nine tubular biomarkers. Conclusion: In a wide range of causes of CKD, adding three urine tubular biomarkers (MCP-1, KIM-1, and EGF) to KFRE improves estimates of risk of CKD progression. Clinical Trial registry name and registration number: NCT03594110.

High-dose inactivated influenza vaccine has been shown to provide protection against influenza that is superior to that with the standard dose. However, data from individually randomized trials on the effectiveness of the high-dose vaccine against severe outcomes are limited. In this pragmatic, open-label, randomized, controlled trial conducted in Denmark during the 2022-2023, 2023-2024, and 2024-2025 influenza seasons, we assigned older adults (≥65 years of age) to receive the high dose of the inactivated influenza vaccine or the standard dose. Data collection relied on nationwide administrative health registries. The primary end point was hospitalization for influenza or pneumonia that occurred from 14 days after vaccination through May 31 of the following year. Of the 332,438 participants who underwent randomization, 166,218 were assigned to receive the high-dose vaccine and 166,220 to receive the standard-dose vaccine. The mean (±SD) age of the participants was 73.7±5.8 years, and 161,538 participants (48.6%) were women. A primary end-point event occurred in 1138 participants (0.68%) in the high-dose group and in 1210 (0.73%) in the standard-dose group (relative vaccine effectiveness, 5.9%; 95.2% confidence interval [CI], -2.1 to 13.4; P = 0.14). Hospitalization for influenza occurred in 0.06% of the participants in the high-dose group and in 0.11% of those in the standard-dose group (relative vaccine effectiveness, 43.6%; 95.2% CI, 27.5 to 56.3); hospitalization for pneumonia occurred in 0.63% and 0.63%, respectively (relative effectiveness, 0.5%; 95.2% CI, -8.6 to 8.8); hospitalization for cardiorespiratory disease in 2.25% and 2.38% (relative effectiveness, 5.7%; 95.2% CI, 1.4 to 9.9); hospitalization for any cause in 9.38% and 9.58% (relative effectiveness, 2.1%; 95.2% CI, -0.1 to 4.3), and death from any cause in 0.67% and 0.66% (relative effectiveness, -2.5%; 95.2% CI, -11.6 to 5.9). The incidence of serious adverse events was similar in the two groups. In this trial, a high-dose inactivated influenza vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia than a standard dose among older adults. (Funded by Sanofi; DANFLU-2 ClinicalTrials.gov number, NCT05517174; EU Clinical Trials Register number, 2022-500657-17-00.).

BACKGROUND: Influenza contributes substantially to disease burden in individuals with heart failure (HF) and is an established trigger of cardiovascular and HF events. Standard-dose inactivated influenza vaccine (SD-IIV) is recommended for HF, though immune responses may be attenuated. High-dose inactivated influenza vaccine (HD-IIV) was developed to enhance immunogenicity, but its effectiveness compared with SD-IIV against hospitalization for influenza and cardiovascular disease by HF status remains uncertain. METHODS: This was a prespecified analysis of a pragmatic, prospective, individually randomized, open-label trial with registry-based end point-evaluation conducted in Denmark across the 2022/2023 to 2024/2025 influenza seasons. Citizens ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Outcomes included hospitalization for influenza-related illness, laboratory-confirmed influenza, any cardiovascular disease, cardio-respiratory disease, and HF, assessed by HF status. Effect of HD-IIV versus SD-IIV in reducing risk of outcomes assessed was expressed as risk ratios. RESULTS: The trial randomized 332 438 participants (48.6% female; mean age, 73.7±5.8 years), including 10 410 with HF at baseline (27.4% female; mean age, 76.0±6.3 years). Overall, HD-IIV was associated with a statistically significant lower incidence of hospitalization for influenza-related illness, laboratory-confirmed influenza, cardio-respiratory disease, cardiovascular disease, and HF compared with SD-IIV. In participants with HF, effect estimates were similar: risk ratio for influenza-related hospitalization was 0.48 (95% CI, 0.20–1.06; P _interaction =0.64), for laboratory-confirmed influenza hospitalization 0.55 (95% CI, 0.29–1.02; P _interaction =0.59), for cardio-respiratory hospitalization 0.89 (95% CI, 0.77–1.02; P _interaction =0.34), for cardiovascular hospitalization 0.86 (95% CI, 0.72–1.02; P _interaction =0.34), and for HF hospitalization 0.82 (95% CI, 0.61–1.11; P _interaction =0.83). Findings were consistent across HF subgroups by disease duration, recency of hospitalization, most recent NT-proBNP (N-terminal pro-B-type natriuretic peptide), and presence of device therapy. CONCLUSIONS: In this prespecified exploratory analysis of the largest individually randomized influenza vaccine trial ever conducted, HD-IIV was associated with lower rates of influenza and cardiovascular hospitalizations compared with SD-IIV, with effect estimates similar across HF status at baseline and HF subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: https://clinicaltrials.gov/study/NCT05517174 .

SUMMARY: Background: The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial evaluated the effects of sixteen potential treatments for patients hospitalised with COVID-19. Dexamethasone (at a dose of 6mg daily), tocilizumab, baricitinib, and the monoclonal antibodies casirivimab-imdevimab and sotrovimab were shown to reduce 28-day mortality in all or specific groups of patients. Here we report the long-term efficacy and safety of all sixteen therapies. Methods: Patients hospitalised with COVID-19 were potentially eligible to join this randomised, controlled, open-label, platform trial. Participants were randomly allocated to receive each trial treatment, or not, on top of usual care. Analyses were by intention to treat comparing each treatment with its own usual care control group. The pre-specified primary long-term follow-up outcome was 6-month all-cause mortality, presented as mortality rate ratios adjusted for baseline age and ventilation status. The key safety outcomes were major non-COVID infection and non-COVID death at 6 months. ISRCTN50189673 and NCT04381936 . Findings: Between 19 March 2020 and 19 March 2024, 48,402 patients were included in RECOVERY COVID-19 treatment comparisons. For each of the treatments previously demonstrated to be effective at 28 days, the early mortality benefit was preserved up to 6 months. Among 6425 patients in the dexamethasone (6mg daily) comparison, 6-month mortality was 34.3% vs 44.4% in the invasive mechanical ventilation group (rate ratio [RR] 0.68; 95% confidence interval [CI] 0.55–0.85; p=0.0006); 27.7% vs 29.2% in the oxygen or non-invasive ventilation group (RR 0.87; 95% CI 0.77–0.99; p=0.034); and 26.1% vs 22.5% in the no oxygen group (RR 1.10; 95% CI 0.89–1.36; p=0.39); test for trend p=0.0024. Among 4116 patients in the tocilizumab comparison, 34.3% vs 38.9% died within 6 months (RR 0.87; 95% CI 0.79–0.96; p=0.0077). Among 8156 patients in the baricitinib comparison, 15.7% vs. 16.6% died (RR 0.89; 95% CI 0.80–0.99; p=0.032). Among 3153 anti-SARS-CoV-2 serum antibody negative patients (the primary analysis population) in the casirivimab-imdevimab comparison, 29.3% vs. 34.7% died (RR 0.87; 95% CI 0.77–0.98; p=0.024). Among 720 patients with high serum nucleocapsid antigen concentration (the primary analysis population) in the sotrovimab comparison, 33.0% vs. 38.6% died (RR 0.78; 95% CI 0.61–1.00; p=0.050). In line with the 28-day results, aspirin, azithromycin, colchicine, convalescent plasma, dimethyl fumarate, empagliflozin, lopinavir-ritonavir, molnupiravir, and nirmatrelvir-ritonavir did not reduce 6-month mortality. Mortality at 6 months was higher with hydroxychloroquine therapy (33.3% vs. 30.2%; RR 1.14; 95% CI 1.02–1.27; p=0.018) and, among hypoxic patients not requiring ventilatory support, with higher dose dexamethasone (initial dose 20mg daily, 22.0% vs. 17.6%, RR 1.34; 95% CI 1.04–1.72; p=0.021). Allocation to dexamethasone 6mg once daily resulted in a small increase in major non-COVID infection within 6 months compared with usual care (21.4% vs. 19.1%; absolute difference 2.2%; 95% CI 0.2–4.5%). We found no evidence that any other treatments increased the risk of major non-COVID infection. Interpretation: In patients hospitalised with COVID-19, dexamethasone (at a dose of 6mg daily in hypoxic patients), tocilizumab (in hypoxic patients with CRP ≥75 mg/L), baricitinib, casirivimab-imdevimab (in seronegative patients), and sotrovimab (in high antigen patients) reduced 6-month mortality. Dexamethasone at a dose of 6mg daily was associated with an increase in major non-COVID infection but there was no evidence of other later emerging harms. Other treatments tested in RECOVERY did not reduce 6-month mortality. Funding: UK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are recommended for use in adults with chronic kidney disease (CKD) and are widely prescribed. SGLT2 inhibition markedly increases urine glucose excretion, which could interfere with laboratory assays. We assessed whether assays for several key urine tubular biomarkers (alpha-1 microglobulin [α1M], dickkopf-3 [DKK-3], epidermal growth factor [EGF], interleukin-18 [IL-18], kidney injury molecule-1 [KIM-1], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], uromodulin [UMOD], and human cartilage glycoprotein-40 [YKL-40]) are affected by glycosuria using urine samples from participants with CKD. Each urine sample was divided into three aliquots, with one serving as control and the other two being spiked with glucose to reach effective concentrations of 28 mmol/l and 111 mmol/l. There was large positive mean bias [95% CI] observed at 28 mmol/l glucose concentration for IL-18 (0.10 [0.01, 0.23]) and YKL-40 (0.40 [0.32, 0.49]). The limits of agreement (LOA) for both biomarkers were wide, spanning >1 unit difference in log-transformed biomarker values. The rest of the biomarkers had narrow LOA. Modest negative mean bias at 28 mmol/l glucose concentration was observed for DKK-3 (−0.02 [−0.04, 0]), KIM-1 (−0.04 [−0.06, −0.02]), and UMOD (−0.08 [−0.11, −0.06]), with similar values observed at 111 mmol/l glucose concentration. There was no evidence of any bias in measurements of α1M, EGF, MCP-1, and NGAL. Glycosuria substantially interferes with IL-18 and YKL-40 measurements, without importantly affecting α1M, DKK-3, EGF, KIM-1, MCP-1, NGAL or UMOD.

BACKGROUND: Influenza vaccination reduces the risk of adverse outcomes in patients with cardiovascular disease (CVD). We sought to evaluate whether the presence of CVD modified the relative effectiveness of the high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in this prespecified analysis of the DANFLU-1 trial (Feasibility of Randomizing Danish Citizens Aged 65–79 Years to High-Dose Quadrivalent Influenza Vaccine Versus Standard-Dose Quadrivalent Influenza Vaccine in a Pragmatic Registry-Based Setting). METHODS: DANFLU-1 was a pragmatic, open-label, randomized feasibility trial of QIV-HD versus QIV-SD in adults aged 65 to 79 years during the 2021/2022 influenza season in Denmark. Vaccines were allocated in a 1:1 ratio. Baseline and follow-up data regarding diagnoses and mortality were obtained from Danish national registers. The trial is registered at Clinicaltrials.gov: NCT05048589. The CVDs assessed included heart failure, ischemic heart disease, atrial fibrillation, and a combined group denoted chronic CVD consisting of the aforementioned diseases, among others. Prespecified outcomes included hospitalizations for pneumonia or influenza, respiratory disease, CVD, cardiorespiratory disease, all-cause hospitalizations, and mortality. Effect modification was tested using interaction terms. RESULTS: The final study population included 12 477 participants (mean age of 71.7±3.9 years and 5877 [47.1%] were female), of whom 2540 (20.4%) had chronic CVD. QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia or influenza (incidence rate ratio [IRR], 0.30 [95% CI, 0.14–0.64]) and all-cause mortality (IRR, 0.51 [95% CI, 0.30–0.86]) regardless of chronic CVD ( P _interaction =0.57 and 0.49, respectively). The relative effectiveness of QIV-HD versus QIV-SD against all-cause hospitalizations was modified in participants with chronic CVD (overall: IRR, 0.87 [95% CI, 0.76–0.99]; no chronic CVD: IRR, 0.79 [95% CI, 0.67–0.92]; chronic CVD: IRR, 1.11 [95% CI, 0.88–1.39]; P _interaction =0.026). No other effect modification was observed by the presence of chronic CVD, heart failure, ischemic heart disease, or atrial fibrillation. CONCLUSIONS: The relative effectiveness of QIV-HD versus QIV-SD was consistent against hospitalizations for pneumonia or influenza and all-cause mortality regardless of chronic CVD. However, the relative effectiveness against all-cause hospitalizations was modified by the presence of chronic CVD. These results should be considered hypothesis generating. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05048589.

Background Sotrovimab is a neutralising monoclonal antibody that has been proposed as a treatment for patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 pneumonia. In the sotrovimab comparison, eligible and consenting patients were randomly allocated to either usual care alone or usual care plus a single 1g dose of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised according to their baseline serum SARS-CoV-2 nucleocapsid antigen concentration as ‘high-antigen’ or ‘low-antigen’, using the median concentration as a cut-off. The primary outcome was 28-day mortality assessed by intention to treat. Secondary outcomes were time to discharge alive from hospital, and, among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings From 4 January 2022 to 19 March 2024, 1723 patients were recruited to the sotrovimab comparison. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. Over 80% of patients were vaccinated, over 80% had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. In the prespecified primary efficacy population of high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60). Interpretation In patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population of patients with a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared with placebo, with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11 000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

SUMMARY: Background: Low-dose corticosteroids (e.g. 6 mg dexamethasone) have been shown to reduce mortality for hypoxic COVID-19 patients. We have previously reported that higher dose corticosteroids cause harm in patients with hypoxia but not receiving ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation), but the balance of efficacy and safety in patients receiving ventilatory support is uncertain. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) assessed multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients receiving ventilatory support were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. Recruitment closed on 31 March 2024 when funding for the trial ended. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ). Findings: Between 25 May 2021 and 9 January 2024, 477 COVID-19 patients receiving ventilatory support were randomly allocated to receive usual care plus higher dose corticosteroids versus usual care alone (of whom 99% received corticosteroids during the follow-up period). Of those randomised, 221 (46%) were in Asia, 245 (51%) in the UK and 11 (2%) in Africa. 143 (30%) had diabetes mellitus. Overall, 86 (35%) of 246 patients allocated to higher dose corticosteroids versus 86 (37%) of 231 patients allocated to usual care died within 28 days (rate ratio [RR] 0.87; 95% CI 0.64-1.18; p=0.37). There was no significant difference in the proportion of patients discharged from hospital alive within 28 days (128 [52%] in the higher dose corticosteroids group vs 120 [52%] in the usual care group; RR 1.04, 0.81-1.33]; p=0.78). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (76 [37%] of 206 vs 93 [45%] of 205; RR 0.79 [95% CI 0.63–1.00]; p=0.05). Interpretation: In patients hospitalised for COVID-19 receiving ventilatory support, we found no evidence that higher dose corticosteroids reduced the risk of death compared to usual care, which included low dose corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Key Points: Frailty, multimorbidity, and polypharmacy overlap and are associated with higher risk of adverse health outcomes in CKD. Empagliflozin was safe, well tolerated, and effectively reduced cardiorenal and hospitalization risk irrespective of these characteristics. Absolute benefits appeared greater in the most frail participants in this post hoc analysis of EMPA-KIDNEY. Background: Sodium-glucose cotransporter-2 inhibitors are recommended treatment for adults with CKD, but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk–benefit profile in a post hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (eGFR ≥20 to 2, or ≥45 to 2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed them for 2 years (median). Additional characteristics analyzed in subgroups were multimorbidity, polypharmacy, and health-related quality of life at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility, and diabetes and then eGFR and other comorbidities. Empagliflozin was generally well tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio, 0.72; 95% confidence interval, 0.64 to 0.82) and all-cause hospitalization by 14% (hazard ratio, 0.86; 95% confidence interval, 0.78 to 0.95), with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy, or health-related quality of life. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. Conclusions: These findings support the use of sodium-glucose cotransporter-2 inhibitors in CKD, irrespective of frailty, multimorbidity, or polypharmacy. Clinical Trial registration number: NCT03594110. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2024_09_23_CJASNSeptember19992.mp3