Albuminuria Downregulation of the Anti-Aging Factor Klotho: The Missing Link Potentially Explaining the Association of Pathological Albuminuria with Premature Death

Ten percent of the adult population has chronic kidney disease (CKD), which is diagnosed when the glomerular filtration rate (GFR) is below 60 mL/min per 1.73 m² or when albuminuria is above 30 mg/day. The numerical thresholds were chosen because they are associated with an increased risk of CKD progression or premature death within a wider scenario of accelerated aging. Indeed, CKD is one of the fastest growing causes of death worldwide. A decreased GFR is associated with the accumulation of uraemic toxins that may promote tissue and organ damage. However, CKD may be diagnosed when the GFR is completely normal, as long as there is pathological albuminuria. A key unanswered question to stem the rise of CKD-associated deaths is whether the association between isolated albuminuria (when the GFR is normal) and premature death is causal. The recent demonstration that albuminuria per se directly suppresses the production of the anti-aging factor Klotho by kidney tubular cells may be one of the first steps to address the causality of the albuminuria–premature death–accelerated aging association. This hypothesis should be tested in interventional studies that should draw from translational science advances. Thus, the observation that albuminuria decreases Klotho production through epigenetic mechanisms implies that Klotho downregulation may persist after the correction of albuminuria, and innovative therapeutic approaches are needed to restore Klotho production. On the basis of recent literature, these may include manipulation of NF-kappaB regulators such as B cell lymphoma 3 protein (BCL-3), and epigenetic regulators such as histone deacetylases, or the repurposing of drugs such as pentoxifylline.