A review: continuous renal replacement therapy for sepsis-associated acute kidney injury

Abstract

Sepsis is a series of systemic inflammatory reactions induced by infection and trauma, which can cause significant organ damage. Continuous renal replacement therapy (CRRT), a new alternative to renal therapy, is a long-term and continuous external blood purification therapy that lasts for 24 h. This procedure can remove metabolic toxins and inflammatory mediators in the body, as well as correct water electrolyte disorders and acid-base and immune imbalances. This article reviews the clinical application of CRRT in the treatment of sepsis-associated acute kidney injury and analyzes its underlying mechanisms in the treatment of sepsis, thereby providing a theoretical basis for the clinical treatment of sepsis.

Highlights

1. Hemodynamic and non-hemodynamic mechanisms underlying sepsis-associated AKI.

2. Inflammatory and oxidative stress factors mediate AKI.

3. CRRT has therapeutic advantages and prospects in AKI.

KEYWORDS:

• Continuity
• renal replacement therapy
• sepsis-associated acute kidney injury
• inflammatory factors
• oxidative stress

Introduction

Sepsis is a systemic inflammatory response syndrome that is caused by infection and trauma. Severe sepsis often leads to septic shock, multiple organ dysfunction syndrome, and even multiple organ failure (Caraballo and Jaimes 2019; Salomao et al. 2019). The patient may also become hemodynamically unstable. Clinically, acute respiratory distress syndrome, acute renal injury, and shock often occur, eventually developing into severe sepsis (Peerapornratana et al. 2019; Font et al. 2020). The kidney is one of the main organs that is susceptible to infection. Kidney damage induced by infection contributes to a significant increase in patient mortality (Rajdev et al. 2020). In the intensive care unit, approximately 35% of patients have acute kidney injury (AKI), while 50% of acute renal failure is secondary to sepsis. Furthermore, the mortality of sepsis patients with AKI is significantly higher than that of non-sepsis patients with AKI (Matsubara et al. 2019; Zhang et al. 2019). AKI has been regarded as an independent risk factor for death in sepsis (Santagada et al. 2019). Compared to intermittent hemodialysis, continuous renal replacement therapy (CRRT) can promote the stability of blood circulation, facilitate the recovery of renal function, and effectively reduce the mortality of patients. Therefore, CRRT has been widely used in the clinical support and treatment of important organs (Hoff et al. 2020).

Pathogenesis of sepsis-associated acute renal failure

The pathogenesis of sepsis-associated AKI is multifactorial, and histopathological examinations are carried out to determine its pathogenesis. However, due to the risks associated with renal biopsy, histopathological examinations are limited in their ability to identify sepsis-associated acute renal failure. At present, the underlying mechanisms of sepsis-associated AKI can be categorized into two groups: hemodynamic and non-hemodynamic.

Hemodynamic mechanisms

During the early stages of AKI, its pathogenesis is thought to be similar to that of ischemia. The decrease in cardiac output or blood pressure in early-stage AKI leads to a decrease in renal perfusion pressure and renal blood flow (RBF), which contribute to a decline in the glomerular filtration rate. Persistent renal ischemia results in the depletion of energy reserves, which can lead to acute tubular necrosis. The resulting exfoliation of renal tubular epithelial cells damages and blocks the renal tubules, resulting in a significant decrease in glomerular filtration rate and urine volume, as well as an accumulation of toxic metabolites (Yoshimura et al. 2020). In animal and human studies of low hemodynamic shock, AKI has been shown to be caused by renal ischemia (Shoho and Kuriyama 2021). Thus, restoring adequate RBF may be an effective way of protecting the kidney (Kirpatovskii et al. 2020).

In contrast, some studies examining severe sepsis or septic shock have reported that renal blood circulation participated in systemic vascular dilation, and the RBF was thus not decreased. Furthermore, their findings have demonstrated that septic RBF did not occur in the renal hypoperfusion model, but instead in a model of sufficient or even increased renal perfusion, suggesting that a decrease in RBF under these circumstances was not the main mechanism of renal injury (Yoshimura et al. 2020). Other studies have reported that the phenomenon separating RBF and renal function may be related to the intrarenal shunt and relaxation of outflow arterioles (Prowle et al. 2012). Although the kidney is well perfused, the diastolic degree of glomerular outflow arterioles is greater than that of the glomerular inflow arterioles. Thus, even with an increase in RBF, the effective filtration pressure and glomerular filtration rate will decrease due to a decrease in the glomerular perfusion pressure (Douvris et al. 2019). Based on this hypothesis, the clinical use of vasodilator drugs would not be beneficial. However, the use of drugs that constrict the bulbar arteriole may be effective in increasing urine volume and improving renal function.

Non-hemodynamic mechanisms

Inflammatory factors

Cytokines have a critical role in the progression of sepsis, which may lead to organ failure. Studies on cytokines and sepsis-associated AKI have demonstrated that acute renal injury was associated with tumor necrosis factor-alpha (TNF-α) and interleukin-1β (Karabulut et al. 2021). In a sepsis-associated AKI model, early blockade of the inflammatory response with antioxidants, such as superoxide dismutase, resulted in significant improvements in the renal perfusion pressure, RBF, and glomerular filtration rate, suggesting that the inflammatory response plays an important role in the pathogenesis of AKI (Aguilera Bazan et al. 2014; Huang et al. 2020). TNF-α is believed to be one of the first inflammatory mediators secreted by the body following bacterial stimulation and is therefore a key inflammatory mediator and initiator in the systemic inflammatory response to sepsis. TNF-α induces and promotes the production of other inflammatory mediators in the body, and its core function is to activate a cytokine cascade in the inflammatory response. This cascade is similar to the positive feedback regulation in neural agitation, stimulating the release of more factors. If not effectively controlled, the damage caused by inflammatory mediators can eventually lead to multi-organ dysfunction syndrome, including AKI. In animal studies, passive immunization with anti-TNF-α antibodies leads to a reduction in renal injury, suggesting that TNF-α has an important role in its pathogenesis (Wu et al. 2021). In recent years, an increasing number of studies have focused on the dysregulation of diastolic and constrictive substances leading to AKI and the ability to improve renal function by antagonizing excessive diastolic and constrictive substances, which suggests that they have a relevant role in AKI pathogenesis.

Oxidative stress

Oxidative stress plays an important role in the development of sepsis-associated AKI. An excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body during sepsis, an imbalance between oxidative and antioxidant systems, as well as an imbalance in oxygen delivery and oxygen demand all contribute to tissue damage (Yu et al. 2020). Increased ROS and RNS levels have been implicated in the development of sepsis-associated AKI. Increased ROS levels promote lipid peroxidation of cell membranes, destroy proteins and nucleic acids, and affect mitochondrial membrane permeability, which induces the release of lysosomal cathepsin D and downregulates the expression of anti-apoptotic protein Bcl-2, ultimately leading to cell necrosis or apoptosis (Al-Harbi et al. 2018).

Energy metabolism

The kidney is a highly metabolic organ. Renal tubular epithelial cells are rich in mitochondria in order to meet the high ATP demands required for renal tubular transport. Sepsis-associated AKI damage to the S2 and S3 proximal tubules is the most significant, since these segments possess the greatest mitochondrial density and highest reabsorption efficiency (Ow et al. 2021). The mitochondrial electron transport chain consists of complexes I–IV and ATP synthase. When the electron transport chain is not damaged, mitochondria produce only a small amount of superoxide free radicals, which can be cleared by manganese superoxide dismutase (MnSOD) in the mitochondrial matrix. However, during sepsis-associated AKI, disruption of the electron transport chain leads to proximal tubular damage, resulting in the inactivation of MnSOD, elevated levels of superoxide free radicals, and accumulation of ROS. ROS accumulation, in turn, causes lipid peroxidation in the mitochondrial inner membrane and the release of proapoptotic proteins, which can exacerbate the progression of sepsis-associated AKI. Alternatively, the accumulation of ROS can cause mitochondrial DNA breaks that lead to mutations in the next generation of mitochondria. In summary, impaired mitochondria form a positive feedback loop with the ROS, continuously exacerbating the cellular damage caused by sepsis-associated AKI (Gatti and Pea 2021). Other studies have shown that damaged mitochondria are unable to provide the energy required for renal tubular recovery in sepsis-associated AKI. As the number of normal mitochondria decreases, the energy metabolism disorder of the renal tubular epithelial cells becomes increasingly serious, further aggravating the condition (Ge et al. 2017).

Overview of CRRT

CRRT is a treatment that continuously and slowly removes impurities and solutes from the patient’s blood through extracorporeal circulating blood purification. CRRT removes metabolic toxins and inflammatory mediators from the body and corrects water-electrolyte disorders, as well as acid-base and immune imbalances, thereby protecting the heart, brain, kidneys, lungs, liver, and other organ systems. CRRT can control hemodynamic stability and plays an important role in regulating nitrogen levels and water-salt metabolism in the blood. Continuous blood purification removes toxins and inflammatory factors from the body, generating a safe environment (Ronco and Reis 2021). Thus, CRRT has a critical and irreplaceable role in the treatment of renal failure and systemic inflammatory response syndrome (Goumenos et al. 2016; Andrei et al. 2021). Compared to intermittent hemodialysis, CRRT has the ability to promote stable blood circulation, facilitate the recovery of renal function, and effectively reduce the morbidity and mortality rate of patients, and is therefore widely used in the clinical support and treatment of vital organs. At present, CRRT mainly includes the following treatment modalities: continuous arteriovenous hemofiltration, hemofiltration-adsorption dialysis, continuous veno-venous hemodialysis, continuous arteriovenous hemodialysis, continuous arteriovenous slow filtration, continuous high-throughput dialysis, continuous arteriovenous hemodialysis filtration, continuous veno-venous hemodialysis filtration, high-volume hemofiltration, continuous veno-venous filtration-venous bypass, continuous veno-venous filtration-extracorporeal membrane oxygenation, and endotoxin adsorption (Houze et al. 2020).

Application of CRRT in the treatment of sepsis-associated AKI

During the treatment of renal diseases, the clinical application of CRRT can effectively remove inflammatory mediators, reduce the concentration of inflammatory mediators in the body, and ensure the balance in the body’s pro-inflammatory/anti-inflammatory system. Thus, CRRT is an ideal therapeutic strategy for the treatment of sepsis in the ICU (Ostermann et al. 2021). In addition, CRRT also leads to improved hemodynamic stability and solute clearance. Sepsis leads to an imbalance in the internal and external environment of the body, as well as a significant disruption in the corresponding production of mediators, while the inflammatory mediators entering the circulatory system may have autocrine and paracrine effects. However, CRRT reduces these adverse effects of sepsis, effectively preventing further development of the inflammatory response, protecting tissue cells from damage by inflammatory factors, inhibiting the death of vascular endothelial cells, improving vascular function and hemodynamics, correcting vascular paralysis caused by sepsis, and improving tissue blood perfusion (Constantinescu et al. 2020). RBF patients presenting with hypercatabolism require adequate calorie and protein supplementation, while water intake needs to be restricted to avoid edema. CRRT can ensure that the high mandatory fluid intake required by the patient is met and that the patient receives adequate nutritional support, allowing for better control of metabolic abnormalities. The application of hemodialysis in RBF patients presenting with cerebral edema can lead to an dialysis disequilibrium syndrome, which can aggravate cerebral edema and even cause brain herniation, seriously threatening the patient’s life. This is due to a decrease in plasma osmolality during hemodialysis or secondary to brain tissue toxicity. CRRT allows for a slow decrease in plasma colloid osmolality, maintaining hemodynamic stability and further protecting brain perfusion pressure to avoid the onset of dialysis disequilibrium syndrome. Most RBF patients presenting with cardiovascular failure cannot tolerate normal hemodialysis due to cardiovascular dysfunction. However, since CRRT involves convective clearance, which is a process of isotonic super-rate and continuous vascular refill, there is no shift in the intracellular fluid associated with changes in the plasma colloid osmotic pressure. Thus, CRRT has good stability and promotes hemodynamic stability in patients (Ronco and Reis 2021).

Other treatments for sepsis-associated AKI

In addition to CRRT, apoptosis inhibition therapy and mitochondria-targeting therapy can also be used clinically in the treatment of sepsis-associated AKI. Therapeutic drugs for inhibiting apoptosis include Fasudil, which activates the PI3K/AKT signaling pathway, thereby reducing cellular apoptosis and playing a protective role in AKI by improving renal function (Tian et al. 2015). Therapeutic drugs that target the mitochondria include SS-31, which can reverse the inactivation of MnSOD, stabilize the inner mitochondrial membrane, promote electron transport chain transport, and accelerate the recovery of ATP levels, thereby protecting renal tubular epithelial cells against damage (Tang et al. 2021).

Outlook

In contrast to conventional intermittent hemodialysis, CRRT removes excess toxins and water from the patient’s body in a more physiological approach, simulating urinary excretion in a sustained and slow manner. CRRT removes metabolic waste, maintains water-electrolyte and acid-base balance, helps to restore kidney function, ensures nutritional intake, helps patients to survive the risk period, and improves prognosis (Yessayan et al. 2021). However, CRRT also has some limitations. For example, due to the slow rate of solute removal, CRRT can be harmful for patients with high potassium levels. Furthermore, since hemodialysis is required to stabilize the condition before application of CRRT, there is an increased time and cost burden associated with CRRT compared to normal dialysis treatment (Mattke et al. 2020). However, as medical and social progress continues in China, the concept of multidisciplinary renal support with CRRT in clinical settings is gaining ground. Blood purification techniques are no longer unique to nephrology, but have become an important tool for many disciplines to improve patient care. Even so, the timing, indications, and clinical implications of patient care remain controversial. During CRRT in critically ill patients, adjustments in anticoagulation modalities, nutrients, and drug supply have an impact on the pathology, physiology and prognosis of the disease, and further research is needed to explore the application of CRRT in various disciplines. In conclusion, blood purification techniques are constantly evolving, and continuing research in this area will further our understanding of CRRT and expand its clinical use to more areas of medicine.

Author contribution statement

All the work was completed by JDX. JDX agrees to be accountable for all aspects of this research. No other researchers were involved in this investigation.

Disclosure statement

No potential conflict of interest was reported by the authors.