Chronic kidney disease (CKD) is increasingly recognised as a complex, multisystem condition that rarely occurs in isolation. This Series paper outlines major advances in therapeutics that target shared inflammatory, meta...Chronic kidney disease (CKD) is increasingly recognised as a complex, multisystem condition that rarely occurs in isolation. This Series paper outlines major advances in therapeutics that target shared inflammatory, metabolic, and fibrotic pathways across CKD, cardiovascular disease, diabetes, obesity, and infection. Novel therapeutics, including SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and GLP receptor agonists, show substantial benefits for slowing CKD progression and improving cardiovascular outcomes, with combination strategies showing additive potential. This Series paper discusses complexities for therapeutic decision-making in CKD, highlighting multimorbidity, frailty, and polypharmacy care as major challenges for implementation in general or primary care settings. We identify under-recognised, groups of patients at high risk with infection and cancer-related CKD, in whom early detection and integrated care could markedly improve outcomes. Finally, we call for more inclusive and representative evidence generation, improved CKD screening within other disease pathways, and coordinated implementation of emerging therapies to reduce the global burden of CKD.
Biological differences exist between males and females in kidney structure and function, leading to sex heterogeneity in the presentation and outcomes of chronic kidney disease (CKD) and response to novel therapeutics. H...Biological differences exist between males and females in kidney structure and function, leading to sex heterogeneity in the presentation and outcomes of chronic kidney disease (CKD) and response to novel therapeutics. However, treatment guidelines ignore sex-specific differences. This Series paper provides an integrated discussion of the complexity of sex differences in the context of kidney health and disease, from biology through clinical characteristics, treatment, evidence generation, and reporting. Throughout, we consider the effect of genetics, epigenetic regulation, and the role of sex hormones. We highlight substantial opportunities that exist for policy makers, scientific organisations, journal editors, funders, and individuals to change the current paradigm. Strategic and systematic acknowledgment, exploration, and reporting of these differences is needed in future research to continue to advance our understanding of pathophysiology, diagnostics, and novel therapeutics for CKD.
Chronic kidney disease affects 788-844 million adults worldwide and is projected to become the fifth leading cause of death by 2040. Global burden estimates remain limited by ascertainment bias and inadequate access to t...Chronic kidney disease affects 788-844 million adults worldwide and is projected to become the fifth leading cause of death by 2040. Global burden estimates remain limited by ascertainment bias and inadequate access to testing, particularly in low-income and middle-income countries. Advances in detection include improved estimation of glomerular filtration rate (GFR) using cystatin C and the recognition of albuminuria as a key marker for screening and risk stratification. Kidney biopsy is improving diagnostic accuracy and prognostic prediction, and multiomics approaches are advancing our understanding of disease mechanisms and hold promise for precision medicine. Advanced imaging and artificial intelligence are enabling non-invasive diagnostics and case detection. Population screening strategies using estimated GFR and albuminuria are increasingly cost-effective, particularly with the availability of novel therapies. Disease-specific prediction models support individualised risk stratification and clinical decision-making. However, inequitable access, limited validation across diverse populations, gaps in biomarker standardisation, and insufficient health-care system capacity constrain implementation globally. Addressing these challenges requires coordinated investment in diagnostics, workforce training, laboratory infrastructure, and health-care system strengthening alongside continued technological advancement.
Shen L, Zhang X, Ji K
… +22 more, Lu L, Wang Q, Guan Q, Yan S, Zhou Y, Yang Y, Huo Z, You J, Ba Y, Ye Y, Chen Y, Wang S, Lv G, Zhang J, Hu X, Yang F, Yu H, Li J, Wang Q, Zhu J, Ji J, ASTRUM-006 Study Group
BACKGROUND: Perioperative chemo-immunotherapy shows variable outcomes in resectable gastric or gastro-oesophageal junction adenocarcinoma. We evaluated the efficacy and safety of neoadjuvant serplulimab with S-1 plus oxa...BACKGROUND: Perioperative chemo-immunotherapy shows variable outcomes in resectable gastric or gastro-oesophageal junction adenocarcinoma. We evaluated the efficacy and safety of neoadjuvant serplulimab with S-1 plus oxaliplatin (SOX) chemotherapy followed by adjuvant serplulimab versus neoadjuvant placebo plus SOX followed by adjuvant SOX in patients with PD-L1-positive, locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma. METHODS: In this randomised, double-blind, multicentre phase 3 ASTRUM-006 study, patients were screened at 75 hospitals in China and Thailand. Eligible patients aged 18-70 years with PD-L1 combined positive score (CPS) ≥5, resectable gastric or gastro-oesophageal junction adenocarcinoma were randomly assigned 1:1 to neoadjuvant serplulimab or placebo (intravenous; 4·5 mg/kg) plus SOX chemotherapy (intravenous oxaliplatin 130 mg/m on day 1, and oral S1 40-60 mg twice daily on days 1-14) for three cycles (cycle length 21 days), followed by adjuvant serplulimab (up to 17 cycles; serplulimab group) or SOX (five cycles; placebo group). The primary endpoint was investigator-assessed event-free survival (defined as the time from randomisation to the occurrence of progressive disease or local or distant recurrence, other new malignancies, or death), with efficacy first evaluated in PD-L1 CPS ≥10, then in the intention-to-treat (CPS ≥5) population. This study is registered with ClinicalTrials.gov, NCT04139135, and is ongoing. FINDINGS: Between Nov 26, 2019, and April 19, 2024, 1646 patients were screened, of whom 588 patients (median age 61·0 years [IQR 55-66]; 124 [21%] female and 464 [79%] male) at 57 hospitals in China were randomly assigned to the serplulimab group (n=292) or placebo group (n=296). With a median follow-up duration of 42·7 months (IQR 24·3-53·6), median event-free survival was significantly longer with serplulimab than with placebo in the PD-L1 CPS ≥10 population (not reached [NR] vs 42·0 months; hazard ratio 0·65 [95% CI 0·47-0·90]; p=0·0082). With a median follow-up of 35·9 months (IQR 23·5-49·4), median event-free survival was also significantly longer with serplulimab than with placebo in the intention-to-treat population (NR vs 35·9 months; 0·73 [95% CI 0·56-0·94]; p=0·015). Grade 3 or worse treatment-related adverse events occurred in 136 (47%) patients in the serplulimab group and 172 (59%) patients in the placebo group; 19 (7%) and 31 (11%) patients in the respective groups discontinued treatment due to treatment-related adverse events. INTERPRETATION: Neoadjuvant serplulimab plus SOX followed by adjuvant serplulimab significantly improved event-free survival and demonstrated a better safety profile compared with neoadjuvant and adjuvant SOX in PD-L1-positive, resectable gastric or gastro-oesophageal junction adenocarcinoma. Extended follow-up for the overall survival data is warranted to confirm a survival advantage of this perioperative strategy with a chemotherapy-sparing adjuvant component for this indication. FUNDING: Shanghai Henlius Biotech.
Lu S, Liu B, Luo Y
… +55 more, Sun L, Wu L, Han Z, Fan Y, Zhao Y, Li X, Xu H, Meng X, Liu Y, Zhang Z, Luo H, Ma X, Ma X, Shi Q, Zhang Z, Yang R, Wang P, Pan P, Ai X, Li J, Pu X, Wang Z, Fang J, He M, He Y, Guo S, Li J, Wang H, Zhang J, Chu Q, Liu X, Ying S, Wu H, Sun H, Ji Y, Zhou M, Cao C, Tang K, Li Z, Li D, Zhang Z, Li J, Zhou J, Yang H, Du Y, Yang H, Shi J, Chen H, Chen Z, Li W, Lu D, Hu M, Wang ZM, Li B, Xia MY
BACKGROUND: Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC). In our previous report of the H...BACKGROUND: Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC). In our previous report of the HARMONi-6 study, we aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. Ivonescimab combined with chemotherapy significantly prolonged progression-free survival compared with tislelizumab plus chemotherapy. Here we report the prespecified interim overall survival analysis. METHODS: HARMONi-6 is a double-blind, randomised, phase 3 trial, which was conducted at 50 hospitals across China. Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Eligible patients were randomly assigned in a 1:1 ratio to receive ivonescimab or tislelizumab, in combination with paclitaxel and carboplatin for four cycles, followed by maintenance ivonescimab or tislelizumab monotherapy. The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Overall survival was a key secondary endpoint; an interim analysis was planned when approximately 225 overall survival events were observed, but it was triggered after 204 overall survival events to meet regulatory deadlines. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrials.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Aug 17, 2023, to Jan 21, 2025, 761 patients were assessed for eligibility, and after 229 exclusions a total of 532 patients were randomly allocated (266 per group). 494 (93%) of patients were male and 38 (7%) of patients were female. The median age was 64 years (IQR 59-69). At data cutoff (Feb 27, 2026), 204 deaths had occurred: 84 (32%) patients in the ivonescimab plus chemotherapy group and 120 (45%) in the tislelizumab plus chemotherapy group. With a median follow-up of 21·4 months (95% CI 20·27-21·91), the median overall survival was 27·9 months (95% CI 27·89-not evaluable [NE]) with ivonescimab versus 23·7 months (20·11-NE) with tislelizumab (hazard ratio for death 0·66 [95% CI 0·50-0·87]; p=0·0017), meeting the prespecified boundary (p<0·0049). The overall survival benefit with ivonescimab plus chemotherapy was consistent across key subgroups. Treatment-related adverse events of grade 3 or higher occurred in 184 (69%) of 266 patients in the ivonescimab group and 156 (59%) of 265 patients in the tislelizumab group. The incidence of grade 3 or higher haemorrhage was seven (3%) of 266 and two (1%) of 265, respectively. INTERPRETATION: Ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with tislelizumab plus chemotherapy in previously untreated patients with advanced squamous NSCLC. This regimen could provide a novel treatment option as first-line treatment in this patient group. FUNDING: Akeso Biopharma.
BACKGROUND: Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone)....BACKGROUND: Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone). We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas. METHODS: frontMIND is a phase 3, randomised, double-blind, placebo-controlled study conducted at 298 centres in North America, South America, Europe, and the Asia-Pacific region. Patients aged 18-80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m intravenous on day 1, cyclophosphamide 750 mg/m intravenous on day 1, doxorubicin 50 mg/m intravenous on day 1, vincristine 1·4 mg/m [maximum 2 mg] intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1-5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1-10), while those in the R-CHOP group received matching placebos. The primary endpoint was investigator-assessed progression-free survival (defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treat population; safety was included as a secondary endpoint among all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling. FINDINGS: Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group. At the time of primary analysis (median follow-up 35·2 months [95% CI 35·0-35·4]), progression-free survival was improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio [HR] 0·75 [95% CI 0·59-0·96]; p=0·0194), with 2-year progression-free survival rates of 71·1% (66·3-75·4) with tafa-len-R-CHOP versus 62·9% (57·9-67·5) with R-CHOP. Interim HR for overall survival was 0·85 (0·63-1·14). The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 [87%] of 443) than with R-CHOP (340 [76%] of 447). Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 [6%]) than with R-CHOP (17 [4%]). However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 [19%] vs 97 [22%]). Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 [16%] of 443) and R-CHOP group (66 [15%] of 447). INTERPRETATION: Progression-free survival was significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide. Overall survival data are immature; follow-up is ongoing. Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survival benefit observed with tafa-len-R-CHOP. Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL. FUNDING: Incyte Corporation.