Distant Organ Dysfunction in Acute Kidney Injury: A Review

Abstract

Acute kidney injury (AKI) is common in critically ill patients and is associated with increased morbidity and mortality. Dysfunction of other organs is an important cause of poor outcomes from AKI. Ample clinical and epidemiologic data show that AKI is associated with distant organ dysfunction in lung, heart, brain, and liver. Recent advancements in basic and clinical research have demonstrated physiologic and molecular mechanisms of distant organ interactions in AKI, including leukocyte activation and infiltration, generation of soluble factors such as inflammatory cytokines/chemokines, and endothelial injury. Oxidative stress and production of reactive oxygen species, as well as dysregulation of cell death in distant organs, are also important mechanism of AKI-induced distant organ dysfunction. This review updates recent clinical and experimental findings on organ crosstalk in AKI and highlights potential molecular mechanisms and therapeutic targets to improve clinical outcomes during AKI.

Keywords: Acute kidney injury (AKI); cardiorenal syndrome (CRS); gut-kidney axis; hepatic dysfunction; lung; microbiota; multi-organ dysfunction; organ crosstalk; reno-cerebral reflex; review.

Figure 1. The impact of acute kidney injury (AKI) on distant organs

Acute kidney injury (AKI) causes hemodynamic-, humoral-, and immunologic changes, which leads to dysfunction of distant organs including lung, heart, brain, liver, intestine and immune system. Abbreviations: AKI, acute kidney injury.

Figure 2. Mechanisms of acute lung injury (ALI) during acute kidney injury (AKI)

Acute kidney injury (AKI) can facilitate development of acute lung injury (ALI) through different mechanisms - volume overload, impairment of cardiac function, systemic inflammation, oxidative stress, increased pulmonary vascular permeability and impaired alveolar fluid clearance. Abbreviations: AKI, acute kidney injury; ALI, acute lung injury; IL, interleukin; TNF-α, tumor necrosis factor alpha; HMGB1, high-mobility group box protein B1; TLR-4, toll-like receptor 4.

Figure 3. Cascade of lung changes after acute kidney injury (AKI)

Following acute kidney injury (AKI), various inflammatory events occur in the alveolar and pulmonary interstitial spaces. Activated endothelium and increased vascular permeability allow leukocytes to transmigrate into pulmonary interstitium. Infiltrated leukocytes aggravate lung injury through inflammatory cytokine/chemokine secretion, increased oxidative stress and cell damage/apoptosis. Epithelial sodium channel and aquaporin 5 expressions are also downregulated following AKI. Protein-rich fluid accumulation in the alveolar space, alveolar hemorrhage and edematous pulmonary interstitial space are observed in acute lung injury (ALI) following AKI. Abbreviations: AKI, acute kidney injury; Na, sodium, H₂O, dihydrogen oxide; AQP, aquaporin; ENaC, epithelial sodium channel; RBC, red blood cell; HMGB-1, high-mobility group box protein B1; TLR-4 - Toll-like receptor 4; ROS, reactive oxygen species. Based on information in Ware & Matthay

Figure 4. Pathophysiology of acute kidney injury (AKI)-induced cardiorenal syndrome

Acute kidney injury (AKI) triggers cardiac dysfunction through various pathophysiological mechanisms, including volume overload, electrolyte and acid-based imbalances, accumulation of uremic toxins, enhanced immune response and activation of sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS). Abbreviations: AKI, acute kidney injury; GFR, glomerular filtration rate; SNS, sympathetic nervous system; RAAS, renin–angiotensin–aldosterone system.