ALL LIFE 2023, VOL. 16, NO. 1, 2163305 https://doi.org/10.1080/26895293.2022.2163305 REVIEW A review: continuous renal replacement therapy for sepsis-associated acute kidney injury Jundong Xu Intensive Care Unit, Yinzhou People’s Hospital, Ningbo City, People’s Republic of China ABSTRACT ARTICLE HISTORY Received 30 August 2022 Sepsis is a series of systemic inflammatory reactions induced by infection and trauma, which can Accepted 29 November 2022 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. KEYWORDS This procedure can remove metabolic toxins and inflammatory mediators in the body, as well as Continuity; renal correct water electrolyte disorders and acid-base and immune imbalances. This article reviews the replacement therapy; clinical application of CRRT in the treatment of sepsis-associated acute kidney injury and analyzes sepsis-associated acute its underlying mechanisms in the treatment of sepsis, thereby providing a theoretical basis for the kidney injury; inﬂammatory factors; oxidative stress 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. Introduction continuous renal replacement therapy (CRRT) can promote the stability of blood circulation, facilitate Sepsis is a systemic inflammatory response syndrome the recovery of renal function, and effectively reduce that is caused by infection and trauma. Severe sepsis the mortality of patients. Therefore, CRRT has been often leads to septic shock, multiple organ dysfunction widely used in the clinical support and treatment of syndrome, and even multiple organ failure (Caraballo important organs (Hoff et al. 2020). and Jaimes 2019; Salomao et al. 2019). The patient may also become hemodynamically unstable. Clini- Pathogenesis of sepsis-associated acute renal cally, acute respiratory distress syndrome, acute renal failure injury, and shock often occur, eventually developing The pathogenesis of sepsis-associated AKI is multifac- into severe sepsis (Peerapornratana et al. 2019;Font torial, and histopathological examinations are carried et al. 2020). The kidney is one of the main organs that out to determine its pathogenesis. However, due to is susceptible to infection. Kidney damage induced the risks associated with renal biopsy, histopatholog- by infection contributes to a significant increase in ical examinations are limited in their ability to identify patient mortality (Rajdev et al. 2020). In the intensive sepsis-associated acute renal failure. At present, the care unit, approximately 35% of patients have acute underlying mechanisms of sepsis-associated AKI can kidney injury (AKI), while 50% of acute renal failure be categorized into two groups: hemodynamic and is secondary to sepsis. Furthermore, the mortality of non-hemodynamic. sepsis patients with AKI is significantly higher than that of non-sepsis patients with AKI (Matsubara et al. Hemodynamic mechanisms 2019;Zhang et al. 2019). AKI hasbeenregardedasan independent risk factor for death in sepsis (Santagada During the early stages of AKI, its pathogenesis is et al. 2019). Compared to intermittent hemodialysis, thought to be similar to that of ischemia. The decrease CONTACT Jundong Xu email@example.com Intensive Care Unit, Yinzhou People’s Hospital, 251 Baizhang East Road, Yinzhou District, Ningbo City, Zhejiang 315040, People’s Republic of China © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 J. XU in cardiac output or blood pressure in early-stage interleukin-1β (Karabulut et al. 2021). In a sepsis- AKI leads to a decrease in renal perfusion pres- associated AKI model, early blockade of the inflam- sure and renal blood flow (RBF), which contribute matory response with antioxidants, such as superoxide to a decline in the glomerular filtration rate. Persis- dismutase, resulted in significant improvements in the tent renal ischemia results in the depletion of energy renal perfusion pressure, RBF, and glomerular filtra- reserves, which can lead to acute tubular necrosis. The tion rate, suggesting that the inflammatory response resulting exfoliation of renal tubular epithelial cells plays an important role in the pathogenesis of AKI damages and blocks the renal tubules, resulting in a (Aguilera Bazan et al. 2014;Huang et al. 2020). TNF-α significant decrease in glomerular filtration rate and is believed to be one of the first inflammatory medi- urine volume, as well as an accumulation of toxic atorssecretedbythe body followingbacterial stimu- metabolites (Yoshimura et al. 2020). In animal and lation and is therefore a key inflammatory mediator human studies of low hemodynamic shock, AKI has and initiator in the systemic inflammatory response to been shown to be caused by renal ischemia (Shoho and sepsis. TNF-α induces and promotes the production Kuriyama 2021). Thus, restoring adequate RBF may be of other inflammatory mediators in the body, and its an effective way of protecting the kidney (Kirpatovskii core function is to activate a cytokine cascade in the et al. 2020). inflammatory response. This cascade is similar to the In contrast, some studies examining severe sepsis or positive feedback regulation in neural agitation, stim- septic shock have reported that renal blood circulation ulatingthe releaseofmorefactors.Ifnot eeff ctively participated in systemic vascular dilation, and the RBF controlled, the damage caused by inflammatory medi- wasthusnot decreased. Furthermore, theirfindings ators can eventually lead to multi-organ dysfunction have demonstrated that septic RBF did not occur in the syndrome, including AKI. In animal studies, passive renal hypoperfusion model, but instead in a model of immunization with anti-TNF-α antibodies leads to a sufficient or even increased renal perfusion, suggesting reduction in renal injury, suggesting that TNF-α has that a decrease in RBF under these circumstances was an important role in its pathogenesis (Wu et al. 2021). not the main mechanism of renal injury (Yoshimura In recent years, an increasing number of studies have et al. 2020). Other studies have reported that the phe- focusedonthe dysregulationofdiastolic andcon- nomenon separating RBF and renal function may be strictive substances leading to AKI and the ability to relatedtothe intrarenal shuntand relaxation of out- improve renal function by antagonizing excessive dias- flow arterioles (Prowle et al. 2012). Although the kid- tolic and constrictive substances, which suggests that ney is well perfused, the diastolic degree of glomerular they have a relevant role in AKI pathogenesis. outflow arterioles is greater than that of the glomeru- lar inflow arterioles. Thus, even with an increase in RBF, theeeff ctivefiltration pressure andglomerular Oxidative stress filtration rate will decrease due to a decrease in the Oxidative stress plays an important role in the devel- glomerular perfusion pressure (Douvris et al. 2019). opment of sepsis-associated AKI. An excessive pro- Based on this hypothesis, the clinical use of vasodila- duction of reactive oxygen species (ROS) and reactive tor drugs would not be beneficial. However, the use of nitrogen species (RNS) in the body during sepsis, an drugs that constrict the bulbar arteriole may be effec- imbalance between oxidative and antioxidant systems, tive in increasing urine volume and improving renal as well as an imbalance in oxygen delivery and oxygen function. demandallcontributetotissuedamage(Yuetal. 2020). Increased ROS and RNS levels have been implicated in the development of sepsis-associated AKI. Increased Non-hemodynamic mechanisms ROS levels promote lipid peroxidation of cell mem- Inflammatory factors branes, destroy proteins and nucleic acids, and aeff ct Cytokines have a critical role in the progression mitochondrial membrane permeability, which induces of sepsis, which may lead to organ failure. Stud- the release of lysosomal cathepsin D and downreg- ies on cytokines and sepsis-associated AKI have ulates the expression of anti-apoptotic protein Bcl-2, demonstrated that acute renal injury was associ- ultimately leading to cell necrosis or apoptosis (Al- ated with tumor necrosis factor-alpha (TNF-α)and Harbi et al. 2018). ALL LIFE 3 Energy metabolism Continuous blood purification removes toxins and The kidney is a highly metabolic organ. Renal tubu- inflammatory factors from the body, generating a safe lar epithelial cells are rich in mitochondria in order to environment (Ronco and Reis 2021). Thus, CRRT meet the high ATP demands required for renal tubular has a critical and irreplaceable role in the treat- transport. Sepsis-associated AKI damage to the S2 and ment of renal failure and systemic inflammatory S3 proximal tubules is the most significant, since these response syndrome (Goumenos et al. 2016;Andrei segments possess the greatest mitochondrial density et al. 2021). Compared to intermittent hemodialy- and highest reabsorption efficiency (Ow et al. 2021). sis, CRRT has the ability to promote stable blood The mitochondrial electron transport chain consists of circulation, facilitate the recovery of renal function, complexes I–IV and ATP synthase. When the electron and effectively reduce the morbidity and mortality transport chain is not damaged, mitochondria pro- rate of patients, and is therefore widely used in the duce only a small amount of superoxide free radicals, clinical support and treatment of vital organs. At which can be cleared by manganese superoxide dismu- present, CRRT mainly includes the following treat- tase (MnSOD) in the mitochondrial matrix. However, ment modalities: continuous arteriovenous hemofil- during sepsis-associated AKI, disruption of the elec- tration, hemofiltration-adsorption dialysis, continu- tron transport chain leads to proximal tubular damage, ous veno-venous hemodialysis, continuous arteriove- resulting in the inactivation of MnSOD, elevated lev- nous hemodialysis, continuous arteriovenous slow fil- els of superoxide free radicals, and accumulation of tration, continuous high-throughput dialysis, contin- ROS. ROS accumulation, in turn, causes lipid perox- uous arteriovenous hemodialysis filtration, continu- idation in the mitochondrial inner membrane and the ous veno-venous hemodialysis filtration, high-volume release of proapoptotic proteins, which can exacer- hemofiltration, continuous veno-venous filtration- bate the progression of sepsis-associated AKI. Alterna- venous bypass, continuous veno-venous filtration- tively, the accumulation of ROS can cause mitochon- extracorporeal membrane oxygenation, and endo- drial DNA breaks that lead to mutations in the next toxinadsorption(Houzeetal. 2020). generation of mitochondria. In summary, impaired mitochondria form a positive feedback loop with the Application of CRRT in the treatment of ROS, continuously exacerbating the cellular damage sepsis-associated AKI caused by sepsis-associated AKI (Gatti and Pea 2021). Other studies have shown that damaged mitochon- During the treatment of renal diseases, the clinical dria areunabletoprovide theenergyrequiredfor application of CRRT can effectively remove inflamma- renal tubular recovery in sepsis-associated AKI. As the tory mediators, reduce the concentration of inflamma- number of normal mitochondria decreases, the energy tory mediatorsinthe body,and ensure thebalance in metabolism disorder of the renal tubular epithelial the body’s pro-inflammatory/anti-inflammatory sys- cells becomes increasingly serious, further aggravating tem. Thus, CRRT is an ideal therapeutic strategy for the condition (Ge et al. 2017). the treatment of sepsis in the ICU (Ostermann et al. 2021). In addition, CRRT also leads to improved hemodynamic stability and solute clearance. Sepsis Overview of CRRT leads to an imbalance in the internal and external envi- CRRT is a treatment that continuously and slowly ronmentofthe body,aswellasasignificantdisruption removes impurities and solutes from the patient’s in the corresponding production of mediators, while blood through extracorporeal circulating blood purifi- the inflammatory mediators entering the circulatory cation. CRRT removes metabolic toxins and system may have autocrine and paracrine eeff cts. inflammatory mediators from the body and cor- However, CRRT reduces these adverse effects of sep- rects water-electrolyte disorders, as well as acid- sis, effectively preventing further development of the base and immune imbalances, thereby protecting the inflammatory response, protecting tissue cells from heart, brain, kidneys, lungs, liver, and other organ damage by inflammatory factors, inhibiting the death systems. CRRT can control hemodynamic stability of vascular endothelial cells, improving vascular func- and plays an important role in regulating nitro- tion and hemodynamics, correcting vascular paralysis gen levels and water-salt metabolism in the blood. caused by sepsis, and improving tissue blood perfusion 4 J. XU (Constantinescu et al. 2020). RBF patients present- the patient’s body in a more physiological approach, ing with hypercatabolism require adequate calorie and simulating urinary excretion in a sustained and protein supplementation, while water intake needs to slow manner. CRRT removes metabolic waste, main- be restricted to avoid edema. CRRT can ensure that the tains water-electrolyte and acid-base balance, helps high mandatory uid fl intake required by the patient to restore kidney function, ensures nutritional intake, is met and that the patient receives adequate nutri- helps patients to survive the risk period, and improves tional support, allowing for better control of metabolic prognosis (Yessayan et al. 2021). However, CRRT abnormalities. The application of hemodialysis in RBF also has some limitations. For example, due to the patients presenting with cerebral edema can lead to slow rate of solute removal, CRRT can be harmful an dialysis disequilibrium syndrome, which can aggra- for patients with high potassium levels. Furthermore, vate cerebral edema and even cause brain herniation, since hemodialysis is required to stabilize the condi- seriously threatening the patient’s life. This is due to tion before application of CRRT, there is an increased adecreaseinplasmaosmolalityduringhemodialysis time and cost burden associated with CRRT com- or secondary to brain tissue toxicity. CRRT allows for pared to normal dialysis treatment (Mattke et al. 2020). a slow decrease in plasma colloid osmolality, main- However, as medical and social progress continues taining hemodynamic stability and further protecting in China, the concept of multidisciplinary renal sup- brain perfusion pressure to avoid the onset of dialysis port with CRRT in clinical settings is gaining ground. disequilibrium syndrome. Most RBF patients present- Blood purification techniques are no longer unique to ing with cardiovascular failure cannot tolerate normal nephrology, but have become an important tool for hemodialysis due to cardiovascular dysfunction. How- many disciplines to improve patient care. Even so, the ever, since CRRT involves convective clearance, which timing, indications, and clinical implications of patient is a process of isotonic super-rate and continuous vas- care remain controversial. During CRRT in critically cular refill, there is no shift in the intracellular uid fl ill patients, adjustments in anticoagulation modali- associated with changesinthe plasma colloidosmotic ties,nutrients,and drug supply have an impact on the pressure. Thus, CRRT has good stability and promotes pathology, physiology and prognosis of the disease, hemodynamic stability in patients (Ronco and Reis and further research is needed to explore the appli- 2021). cation of CRRT in various disciplines. In conclusion, blood purification techniques are constantly evolving, andcontinuingresearchinthisareawillfurther our Other treatments for sepsis-associated AKI understanding of CRRT and expand its clinical use to In addition to CRRT, apoptosis inhibition therapy more areas of medicine. and mitochondria-targeting therapy can also be used clinically in the treatment of sepsis-associated AKI. Author contribution statement Therapeutic drugs for inhibiting apoptosis include Fasudil, which activates the PI3K/AKT signaling path- All the work was completed by JDX. JDX agrees to be way, thereby reducing cellular apoptosis and playing accountable for all aspects of this research. No other a protective role in AKI by improving renal function researchers were involved in this investigation. (Tian et al. 2015). Therapeutic drugs that target the mitochondria include SS-31, which can reverse the Disclosure statement inactivation of MnSOD, stabilize the inner mitochon- drial membrane, promote electron transport chain No potential conflict of interest was reported by the authors. transport, and accelerate the recovery of ATP levels, thereby protecting renal tubular epithelial cells against References damage (Tang et al. 2021). Aguilera Bazan A, Perez S, Banuelos B, Alonso-Dorrego JM, DiezJ,DelaPenaJ. 2014. Incidence and management of iso- lated renal injury and polytrauma patients. 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Frontiers in Life Science
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Published: Dec 31, 2023
Keywords: Continuity; renal replacement therapy; sepsis-associated acute kidney injury; inflammatory factors; oxidative stress