AKI - Damage To The Kidneys Also Damage Other Organs!

AKI - Acute Kidney Injury, predominantly in the kidneys but can accumulate in other organs, resulting in damage to distant organs. It can be not only the triggering factor causing MODS but also one of the manifestations of MODS caused by other diseases. The interaction between organs is called crosstalk. This is very common in clinical practice, such as cardiorenal syndrome, hepatorenal syndrome, brain-heart syndrome, brain-gastrointestinal syndrome...etc.

Click to cistanche benefits and side effects for acute kidney injury

There are many concepts of clinical syndromes, such as ARDS acute respiratory distress syndrome. Syndrome emphasizes synthesis, that is, the diversity, multiplicity, recruitment, etc. of organ dysfunction. The fatality rate of all syndromes must not be the primary disease, it must be MODS, such as the cause of death of ARDS, the most common cause of death is not respiratory failure, but MDOS.

As far as AKI is concerned, can it also be called: "acute kidney injury syndrome"? It is very common for AKI to cause remote organ damage. Before the concept of AKI, there were concepts such as uremic encephalopathy and uremic cardiac insufficiency. Therefore, the understanding of AKI cannot be considered from the perspective of the kidney alone, but treatment measures should be considered in combination with other organ functions.

This is not unfamiliar. The comprehensiveness and integrity in critical illness thinking mean not looking at the function of a single organ but comprehensively evaluating the interaction of the functions of the whole body. Changes in organ function can be accompanied by improvements or deterioration in other organ functions. The dialectical materialistic thinking of general and particular, connection and development, contradiction and unity is also applicable to clinical severe thinking.

Kidney damage, with damage to other organs

Organ-organ interactions are an important part of human biology. In critically ill patients, damage to one organ often affects other organs. Improving Kidney Outcomes Global Organization (KDIGO) diagnostic criteria reflect acute kidney injury (AKI) characterized by an acute decline in glomerular filtration rate, which can be diagnosed by elevated serum creatinine and/or oliguria. AKI can lead to fluid retention, electrolyte disturbances, metabolic acidosis, and altered drug pharmacokinetics. Clearance of inflammatory mediators is reduced, leading to a marked increase in proinflammatory load [1]. This, coupled with the accumulation of uremic toxins, leads to endothelial damage and increased vascular permeability [2]. In addition to the loss of renal function, renal stress and/or renal injury (subclinical AKI), which may precede the diagnosis of AKI, may also induce inflammation and have long-term consequences. These consequences may vary depending on the underlying etiology of AKI.

This article presents a kidney-centric view of the impact of AKI on vital organ function. Although AKI may affect almost any organ in the body, this review will focus on the most documented interactions and clinically relevant organs.

AKI and the immune system

Clinical data suggest that AKI is associated with subsequent immune system dysregulation, leading to a significantly increased risk of sepsis and transformation from AKI to chronic kidney disease (CKD). Molecular and cellular effectors may play a role in AKI-associated inflammation. First, AKI has profound effects on cytokine homeostasis. During systemic inflammation, the loss of renal function may lead to decreased clearance of cytokines, resulting in increased levels of inflammatory molecules, further aggravating systemic inflammation [1]. In experimental models, several inflammatory cytokines including IL6, IL8, and TNF-α are elevated during AKI. In the clinical setting of trauma, the plasma levels of IL6, IL8, IL1ra, and chemoattractant protein-1 in AKI patients were significantly higher than those in non-AKI patients. In addition, some studies [5] suggest that renal tubular cells may also release inflammatory cytokines during AKI. Second, impaired neutrophil recruitment associated with AKI may affect inflammatory responses, suggesting that AKI may induce anti-inflammatory effects. Experimental analysis revealed that the rolling and migrating abilities of neutrophils [6] were impaired.

AKI and the heart

Cardiorenal syndrome (CRS) defines a complex bidirectional interaction between the heart and kidneys, and CRS type 3 defines cardiac dysfunction due to AKI [7]. The pathophysiological mechanism of AKI leading to acute cardiac dysfunction is still unclear. Some experimental data suggest that early cardiac injury in AKI may be directly triggered by inflammatory mediators, oxidative stress, and upregulation of the neuroendocrine system. Fluid overload is particularly important in physiological disorders associated with loss of renal function because it increases preload and stretches cardiomyocytes, which reduces contractility and increases work demand. In patients with acidemia, acid accumulation may alter protein structure and impair normal function, resulting in decreased myocardial contractility through altered beta-receptor expression and abnormal handling of intracellular calcium. Electrolyte disturbances caused by AKI can cause cardiac arrhythmias, thereby reducing cardiac output and increasing the risk of thrombotic events in patients. In addition, both renin-angiotensin-aldosterone and the central nervous system are activated in AKI, leading to increased fluid retention and increased pre-and post-loading [7]. In terms of uremia, although little is known about the effects of uremic toxins on cardiac function in patients with AKI, associations with cardiovascular toxicity have been demonstrated in CKD [2]. In addition, AKI can also lead to changes in the pharmacokinetics and pharmacodynamics of cardiovascular drugs.

AKI and the lungs

The effects of AKI on the lungs may be related to immune-mediated effects, fluid retention, and electrolyte abnormalities [8]. In animal models of renal ischemia-reperfusion injury (IRI), the inflammasome in the lung and lung metabolism reflecting oxidative stress and energy expenditure are altered. Furthermore, reduced lung expression of ENaC, Na, k-ATPase, and aquaporin-5 was observed in these models, thereby affecting alveolar fluid absorption [10]. In addition, fluid retention increases extravascular lung water, which increases interalveolar fluid content, resulting in impaired oxygenation. Clinical studies have shown that AKI is associated with the severity of pneumonia and sepsis. In the setting of AKI, the duration of mechanical ventilation and mortality are increased in patients with acute respiratory distress syndrome [8]. In addition, metabolic acidosis requires increased ventilator drive and tidal volumes for respiratory compensation, increasing the risk of spontaneous and ventilator-associated lung injury. This may be of particular interest in patients with COPD, where renal compensation of respiratory acidosis is critical.

AKI and the gut

Since the GI tract contains hundreds of species of microbiota and more than half of the body's immune cells, it is the center of homeostasis. In an experimental animal model of IRI, changes in the gut microbiota persisted over 24 hours. This dysbiosis reduces the number of bacterial fermentation products in the lumen, such as short-chain fatty acids (SCFAs), which play a key role in reducing inflammation and gut-organ interactions, thereby increasing inflammation. Experimental models of AKI have also shown infiltration and activation of innate immune cells in the gut wall, with lymphocytes having a stronger inflammatory phenotype. It was hypothesized that AKI-associated fluid overload and uremia could alter epithelial tight junctions and increase intestinal permeability [3]. In conclusion, microbiota dysbiosis, intestinal wall edema, and inflammation are the main consequences of AKI on intestinal function and permeability. Subsequent entry of pathogens and endotoxins into the circulation further enhances systemic inflammation and renal injury. AKI-induced dysbiosis may have played a key role in the transition from AKI to CKD. Other long-term effects reported include an increased risk of upper gastrointestinal bleeding in AKI requiring renal replacement therapy (RRT). Recent innovative approaches targeting the microbiota aim to modulate AKI-associated inflammation.

AKI and the Brain

Encephalopathy is the main symptom of uremia, which is partly related to blood urea nitrogen level. Although complete uremia is a rare event in well-treated AKI patients, accumulation of even low levels of uremic toxins may impair cognitive function in critically ill patients more than in CKD patients. progress is faster [2]. In critically ill adults, AKI KDIGO stages 2 and 3 were associated with a nearly 2-fold increased risk of delirium and coma [12]. AKI in preterm infants is associated with brain damage, especially to the cerebellum [13]. AKI-related encephalopathy may result from elevated systemic cytokine levels and increased oxidative stress in the brain, which is further enhanced by the stimulation of renal sympathetic afferents. These factors may also play a role in the changes in the blood-brain barrier observed in animal experiments, an effect that may be exacerbated by changes in the expression of aquaporins 1 and 4. Finally, the altered metabolism of centrally active drugs must be considered.

AKI and the liver

Unlike hepatorenal syndrome, the impact of AKI on liver function is unclear. Small animal models show pathological changes in liver tissue after renal IRI or nephrectomy. Its main features are tissue infiltration of inflammatory cells and inflammatory mediators such as TNF-α, IL-6, hepatocyte injury and necrosis, and oxidative stress [14]. Recently, transient elevations of liver enzymes, such as amino acid transferases, were observed after ischemic AKI in pigs. Interestingly, changes in liver tissue were only mild and completely disappeared after 5 weeks, suggesting moderate and transient damage [15]. However, AKI still has clinical significance on liver function. Loss of renal function may affect hepatic cytochrome enzyme systems through metabolic acidosis and uremia, resulting in altered drug clearance. In oliguric AKI, fluid accumulation can also be secondary to hepatic congestion and failure [14].

AKI affects distant organs through multiple pathways, such as cellular and molecular effect-mediated inflammatory responses, metabolic and hemodynamic changes, and neuroendocrine systems. When the kidney is damaged, distant organs are also damaged, which can lead to AKI-related mortality and morbidity. Interventions aimed at mitigating kidney-organ interactions may be considered to improve patient outcomes. However, this requires a better understanding of organ-organ interactions, which so far have mainly relied on animal models or CKD patients, without explaining the cause and severity of AKI. A distinction also needs to be made between damage caused by loss of kidney function and damage to the kidney itself.

for more information: Ali.ma@wecistanche.com