The concept of cardiovascular-kidney-metabolic (CKM) syndrome integrates cardiovascular, kidney and metabolic disorders into a single pathophysiological continuum characterized by chronic inflammation, oxidative stress, fibrosis and progressive organ dysfunction. A central driver of CKM syndrome progression is inappropriate activation of the aldosterone-mineralocorticoid receptor (MR) pathway, which promotes adverse remodelling of the heart, kidney, vasculature, adipose tissue, liver and pancreas. Steroidal MR antagonists (MRAs) and non-steroidal MRAs mitigate maladaptive MR signalling and improve cardiorenal outcomes. Compared with steroidal MRAs, non-steroidal MRAs such as finerenone provide enhanced tissue selectivity and favourable safety profiles. Finerenone has been shown to reduce cardiovascular and renal events in patients with chronic kidney disease (CKD) and in patients with heart failure. Aldosterone synthase inhibitors represent a complementary approach that suppresses aldosterone production upstream of MR activation and has shown promising results in resistant hypertension and CKD. Preclinical and clinical data indicate that combined strategies targeting the aldosterone-MR axis can attenuate cardiorenal remodelling, insulin resistance and organ injury, offering a comprehensive therapeutic approach. Ongoing trials will clarify the efficacy of these combined therapies in non-diabetic CKD, resistant hypertension and broader CKM syndrome populations. Overall, targeting the aldosterone-MR pathway represents a central strategy to reduce organ dysfunction, improve metabolic homeostasis and limit progression of CKM syndrome.

Frailty is highly prevalent in patients with chronic kidney disease (CKD) and is associated with increased mortality, hospitalization and disability and with poorer quality of life. Despite its prognostic importance, substantial knowledge gaps remain with regard to the optimal tools for assessing frailty in CKD settings, the extent to which frailty can be reversed through targeted interventions, and how frailty should inform decision-making between conservative kidney management and kidney replacement therapy (KRT). This consensus report provides 63 consensus statements across four domains covering the assessment of frailty, interventions aimed at targeting the modifiable contributors to frailty in patients with CKD, considerations related to conservative kidney management and KRT, and the management of stage 5 CKD in the presence of frailty. Key recommendations include the need for routine frailty screening using multi-dimensional tools; the implementation of interventions to target physical activity with a focus on resistance training, adequate dietary protein intake, medication optimization and comprehensive geriatric assessment; a frailty-informed, person-centred framework for shared decision-making that emphasizes transparent communication, goal elicitation and cultural safety; and flexible KRT delivery - including less intensive dialysis schedules, assisted home dialysis and transplant eligibility assessment - guided by serial frailty measurement. The report concludes with priority research questions and a patient partner's reflections on the co-production of consensus statements.

Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.

Despite treatment advances, chronic kidney disease (CKD) remains an incurable, progressive disease affecting ~850 million people worldwide. Kidney ageing and CKD have many common features, including capillary and epithelial cell loss, increased fibroblast numbers, interstitial fibrosis and chronic immune infiltrates. Consequently, identifying pathways driving the fibrosis and loss of homeostasis shared in both states is a major research priority. Cellular senescence, a cell state characterized by generally irreversible growth arrest with an altered secretory phenotype, is highly conserved across all multicellular organisms. 'Acute' senescence induction with prompt physiological clearance is important for development, contributes to adaptive repair in response to organ injury, and represents a defence against neoplasia. However, the increased numbers of senescent epithelial cells associated with human kidney ageing and CKD include 'chronic' senescent cells, which have been implicated as drivers of kidney dysfunction and fibrosis. Experimental evidence links chronic senescence to kidney leukocyte recruitment and myofibroblast activation. Moreover, pre-clinical studies of senescent cell depletion show extended healthy lifespan, preserved function and reduced fibrosis in multiple organs, including the kidney. Here, we examine current evidence of senescence as a driver of kidney disease and its potential as a therapeutic target.

Primary cilia are microtubule-based organelles that function as cellular antennae, integrating diverse signalling pathways essential for tissue development and function. Dysregulation of ciliary signalling is linked to a broad spectrum of disorders known as ciliopathies, which affect most tissues and organs in the body. Primary cilia are dynamic hubs in which selective trafficking and compartmentalization of receptors, effectors and second messengers shape the strength, duration and specificity of cellular responses. Intraflagellar transport, ciliary gating and cargo adaptors establish and dynamically remodel ciliary composition, enabling signalling through Hedgehog, G-protein-coupled receptors, transient receptor potential proteins, receptor tyrosine kinases and the TGFβ superfamily to coordinate developmental patterning, cell proliferation and differentiation, metabolism and tissue homeostasis. Disruption of ciliary architecture, trafficking or signalling can therefore produce diverse and tissue-specific disease phenotypes, including polycystic kidney disease, retinal degeneration, skeletal abnormalities, cardiovascular diseases, neurodevelopmental disorders and obesity. Emerging evidence indicates that cell-type-specific and temporally dynamic ciliary signatures determine signalling competence and disease susceptibility. Defining these signatures and the mechanisms that regulate their plasticity could lead to new therapeutic opportunities for ciliopathies and other cilia-associated diseases.

Kidney disease is a growing global public health concern that is associated with high rates of severe morbidity and mortality. Accumulating preclinical and clinical evidence suggests that ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, drives the pathogenesis and progression of diverse kidney disorders, including acute kidney injury, chronic kidney disease, renal cell carcinoma and autosomal-dominant polycystic kidney disease. Ferroptosis of renal tubular epithelial cells and intrarenal immune cells engages complex crosstalk with other regulated cell death pathways, amplifying responses and aggravating renal tissue damage. Several biomarkers of early kidney injury, such as the iron regulator NGAL and the phosphatidylserine-binding protein KIM1, are associated with features of ferroptotic cell death, suggesting their potential utility as indirect indicators of early ferroptotic lesions in the kidney. Furthermore, multimodal imaging platforms that integrate optical, magnetic resonance, photoacoustic and radionuclide techniques enable specific in vivo detection of ferroptotic hallmarks, facilitating early diagnosis of kidney lesions. Numerous preclinical studies have identified a diverse range of synthetic small-molecule agents, natural phytochemicals and metabolic modulators that are able to modify ferroptotic signalling. These agents have been shown to mitigate renal parenchymal injury or suppress the proliferation of malignant kidney cells, robustly establishing ferroptosis as a promising therapeutic target for kidney diseases.

The proximal tubule maintains a robust endocytic pathway that is necessary for the recovery of proteins and vitamins from the ultrafiltrate and for the rapid regulation of ion transport. The large multiligand receptor megalin is essential to this process. In the absence of functional megalin, membrane and fluid flux through endocytic compartments is profoundly compromised, whereas the binding of filtered drugs to megalin is a major cause of nephrotoxicity. Insights into the structure of megalin offers clues as to how megalin might drive endocytic dynamics through pH-dependent conformational rearrangements, and findings from focused ion beam-scanning electron microscopy and machine learning-assisted segmentation challenge the traditional model of proximal tubule endocytosis and instead support a model in which a continuous network of dense apical tubules, together with the endoplasmic reticulum, regulates the control of ligand passage, fission and dissociation. In addition to its function as an endocytic receptor, megalin maintains proximal tubule function through other mechanisms. Genomic analyses and animal studies show that predicted alterations in megalin expression have complex effects on disease progression and protection. Consistent with these observations, megalin expression affects proximal tubule transcription and cell metabolism, with important consequences for disease pathology.

Heat exposure is an emerging threat to kidney health, although the mechanisms and magnitude of the problem are incompletely understood. Epidemiological data consistently link hot temperatures with increased kidney morbidity, and heat-stress kidney injury is associated with chronic kidney disease (CKD) in some occupational and agricultural studies. However, the extent to which increasing ambient temperatures will contribute to greater incidence, prevalence and progression of CKD in broader populations is not well characterized. As global temperatures and heatwave frequency increase, people with existing CKD might face dual threats of acute morbidity during heat events and the possibility of accelerated decline in kidney function. Structural determinants, such as housing quality, occupational exposure and access to cooling, compound background physiological vulnerability due to age and comorbidities. Despite this risk, evidence guiding individualized mitigation of heat risk for people with CKD is extrapolated from what is known about how healthy volunteers respond to heat stress. Preventing the growing burden of heat-related kidney injury demands urgent climate action alongside a coordinated kidney health response, with global research collaboration and integration of clinical and societal strategies targeting patient education, context-specific clinical guidance and strong policy responses addressing health inequities and climate resilience.

Acute kidney injury (AKI) is a major risk factor for the subsequent development and progression of chronic kidney disease (CKD), particularly when kidney repair is incomplete or maladaptive. The repair trajectory after kidney injury is primarily determined through the interconnected responses of tubular epithelial cells (TECs), immune cells and fibroblasts. Within this network, TECs act as sentinels of tissue injury and initiators of the repair cascade. After AKI, TECs can undergo regulated cell death programs, whereas surviving cells adopt divergent states that either support regeneration or promote maladaptive repair. In successful repair, surviving TECs proliferate, expand and restore tubular integrity. By contrast, failed repair is characterized by persistent cell-cycle arrest, cellular senescence and the secretion of pro-inflammatory and pro-fibrotic mediators. The signals that are released by injured and maladaptively repaired tubules consequently shape the recruitment and activation of immune cells, which can mediate tissue regeneration or perpetuate inflammation and fibroblast activation. Ultimately, aberrant TEC and immune-cell activation converges in the sustained activation of fibroblasts and the deposition of excess extracellular matrix via cellular crosstalk - the common final pathway of maladaptive repair - which drives the progression of AKI to CKD over time.

Chronic kidney disease (CKD) is a leading cause of premature death due to the loss of kidney function and development of kidney failure, and because of attendant major adverse cardiovascular events. High-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation, is associated with increased risks of cardiovascular events and CKD progression. CKD is characterized by a pro-inflammatory state with upregulation of inflammatory pathways and disruption of anti-inflammatory mechanisms. The resulting systemic inflammation, along with local tissue-based inflammatory mechanisms, are key contributors to kidney damage, atherosclerosis and cardiac dysfunction. As a result, a series of inflammatory pathways and mediators have emerged as potential therapeutic targets for CKD and its major cardiovascular complications. Investigational treatments that have targeted inflammation include inhibition of apoptosis signal-regulating kinase-1 (ASK1) by selonsertib, Janus kinase (JAK) 1/2 inhibition with baricitinib, protein kinase C-β (PKCβ) inhibition with ruboxistaurin, nuclear factor erythroid 2-related factor 2 (Nrf2) activation with bardoxolone, phosphodiesterase inhibition with pentoxifylline and monoclonal antibodies against IL-1β and IL-6. Furthermore, proven therapies for CKD, including renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid antagonists, possess anti-inflammatory properties that might contribute to their previously established clinical benefits.