Human serum albumin, the most abundant protein in human plasma, exerts a multitude of physiological functions that extend beyond its canonical roles in oncotic pressure and solute transport. It acts as a dynamic interface in redox regulation, toxin clearance, immune modulation and pharmacokinetics. In chronic kidney disease, dialysis and transplantation, albumin has diagnostic and therapeutic relevance far surpassing that of a nutritional marker. Emerging insights into the structure–function relationships of albumin, including its binding dynamics, redox isoforms and post-translational modifications, challenge the current paradigm of albumin in chronic kidney disease, which focuses on preserving quantity, and suggest that a shift towards restoring quality might have clinical benefits. Here, we propose two new conceptual frameworks, the ‘albumin paradox’, which reconsiders albumin removal during dialysis as a potentially therapeutic mechanism, and the ‘inflammation-mitigation hypothesis’, which positions albumin functionality as a target in extracorporeal immune modulation. Integrating biophysical, pathophysiological and clinical perspectives, we aim to reframe albumin from a merely passive bystander and laboratory parameter to a modifiable determinant of systemic health and disease. Albumin has roles in toxin transport, antioxidant defence and inflammatory regulation that extend beyond its use as a nutritional marker. Here, the authors discuss changes in albumin abundance and quality across chronic kidney disease and kidney failure, and consider the potential therapeutic benefits of controlled albumin removal during dialysis.
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation leading to kidney failure. Mutations in PKD1 or PKD2, encoding polycystins 1 and 2, underlie most cases of ADPKD. Tolvaptan remains the only approved therapy but has limited efficacy and tolerability, underscoring the need for a deeper mechanistic understanding of disease pathogenesis. Polycystins function as cation channels in the primary cilium — a sensory organelle implicated in renal epithelial development and homeostasis. Pioneering genetic studies have established that cilia loss derepresses a cilia-dependent cyst activation programme, revealing the cilium as an active signalling compartment that restrains cystogenesis triggered by polycystin dysfunction. Structural and ciliary trafficking studies have illuminated how cilia-dependent signals drive cystogenesis in development and adult contexts, whereas ciliary length regulation offers a tractable entry point for identifying ciliary effectors. Extraciliary transcriptional and post-transcriptional pathways cooperate with ciliary signalling to modulate disease progression, often through components that serve distinct compartmental functions. Notably, both ciliary and transcriptional effectors converge on mitochondrial metabolism as a critical checkpoint, revealing an integrated cilium–metabolism axis whose disruption facilitates cystogenesis. Together, this integrated structural, functional and regulatory framework for cilia-regulated ADPKD pathogenesis points towards ciliary trafficking machinery and metabolic checkpoints as actionable therapeutic targets. Autosomal-dominant polycystic kidney disease is predominantly caused by mutations in PKD1 or PKD2, which encode polycystins 1 and 2. Cilia loss derepresses a cilia-dependent cyst activation programme, identifying the cilium as an active signalling compartment that restrains cystogenesis triggered by polycystin dysfunction. This Review describes current understanding of the mechanisms that underlie cyst initiation and progression by cilia.
Clinical research consent forms commonly state that participants may receive no direct benefit, which reflects the uncertainty that surrounds investigational interventions. Yet research participation can offer other advantages, including earlier diagnosis, closer monitoring and referral to care — particularly where routine healthcare access is limited. Ethical frameworks should distinguish benefits of the intervention from those that arise from participation itself.
