Molecular Mechanisms of AKI in the Elderly: From Animal Models to Therapeutic Intervention

Abstract

Acute kidney injury (AKI), a critical syndrome characterized by a sudden reduction of renal function, is a common disorder among elderly patients particularly in Intensive Care Unit (ICU). AKI is closely associated with both short- and long-term mortality and length of hospital stay and is considered a predictor of chronic kidney disease (CKD). Specific hemodynamic, metabolic, and molecular changes lead to increased susceptibility to injury in the aged kidney; therefore, certain causes of AKI such as the prerenal reduction in renal perfusion or vascular obstructive conditions are more common in the elderly; moreover, AKI is often multifactorial and iatrogenic. Older patients present several comorbidities (diabetes, hypertension, heart failure) and are exposed to multiple medical interventions such as the use of nephrotoxic contrasts media and medications, which can also trigger AKI. Considering the emerging relevance of this condition, prevention and treatment of AKI in the elderly should be crucial in the internist and emergency setting. This review article summarizes the incidence, the risk factors, the pathophysiology, the molecular mechanisms and the strategies of prevention and treatment of AKI in elderly patients.

Keywords: acute kidney injury; elderly; intensive care; kidney aging; mortality; renal replacement therapy; risk factors; tubular senescence.

Figure 1

Principal risk factors of AKI in the elderly. A large collection of factors can predispose elderly to AKI. Between them, the most important are the physiological aging of the kidney that is associated to common anatomical and functional changes and the pathological aging correlated to a wide spectrum of comorbidities (such as such as hypertension, diabetes mellitus, heart disease, CKD). Other exogeneous factors include the poor/good outcome of medical interventions and the consequent prolonged hospitalization. Furthermore, nephrotoxic drugs therapies as the contrast media for radio analysis can increase susceptibility to AKI in older patients. The failure to compensate an episode of AKI can lead to higher risk to progression to CKD and depending from severity also of mortality. NSAID, Nonsteroidal anti-inflammatory drug, ACE Angiotensin-converting enzyme.

Figure 2

Central mechanisms underlying the aging kidney and the increased susceptibility to AKI. Several molecular mechanisms are involved in the aging kidneys from intrinsic genetic and epigenetic changes, to cellular senescence, systemic complement activation, the release of uremic toxins and AGE, the impairment of Angiotensin II/ RAS axis (indicated in blue).These events affected the renal homeostasis and the ability to response to AKI injury leading to common kidney alterations at tubular level (as the decline regeneration) and endothelial level (with the microvascular dysfunction, the arterial stiffness and the vascular calcification) (indicated in pink). Oxidative stress is a central mediator in renal aging and should be encountered as initial cause and chronic inducer of AKI in elderly by the time. Abbreviations: SASP Senescence Associated Secretory Phenotype, BMP-2 Bone morphogenetic protein 2, AGE Advanced Glycation End Products, RAGE Receptor for Advanced Glycation End Products, ROS reactive oxygen species, PGC-1α Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, COX2 cytochrome c oxidase subunit 2.