Circadian rhythms and sleep disturbances: a conceptual perspective with implications for autosomal dominant...

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by cyst formation, kidney enlargement, and extrarenal complications. While the role of genetic mutations in PKD1, PKD2, and other minor genes is well established, the influence of circadian rhythms and sleep disturbances on disease progression remains underexplored. The circadian timing system, coordinated by the central clock in the suprachiasmatic nucleus and synchronized with peripheral clocks in the kidneys, regulates key physiological processes, including glomerular filtration rate (GFR), sodium handling, blood pressure, and hormone secretion. In ADPKD, circadian disruption driven by intrinsic molecular alterations and exacerbated by sleep disorders contributes to sympathetic nervous system activation, renin-angiotensin-aldosterone system (RAAS) dysregulation, and elevated vasopressin levels, all of which accelerate cyst growth and hypertension. Mechanistic links also involve the activation of the mTOR pathway, impaired fatty acid oxidation, and altered gut microbiota composition. These disturbances impair kidney function and increase the risk of cardiovascular disease. Chronotherapy and targeted sleep hygiene interventions offer promising adjunctive strategies for mitigating circadian misalignment in ADPKD. Timed administration of antihypertensives, diuretics, and disease-modifying agents, such as tolvaptan, along with melatonin supplementation, structured light exposure, and optimized physical activity patterns, may enhance therapeutic efficacy and improve quality of life (QoL). Future research should prioritize longitudinal and interventional studies incorporating circadian biomarkers to evaluate the impact of aligning therapeutic interventions with biological rhythms on kidney and cardiovascular outcomes in ADPKD.