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Ultrasonographic assessment of renal microcirculation is a new vision for the treatment of intensive care unit associated acute kidney injury

European Journal of Medical Research volume 29, Article number: 115 (2024) Cite this article

Key points

  • Microcirculatory impairment is a key pathogenetic mechanism in acute kidney injury associated with severe disease.

  • CEUS is a "microscope" of the renal microcirculation.

  • CEUS quantitatively assesses the renal microcirculation to help guide hemodynamic therapy in critical care-related acute kidney injury.

  • CEUS is challenging but necessary to differentiate regional blood flow within the kidney.

  • CEUS parameters can be used as sensitive indicators to assess the prognosis of AKI.

Introduction

Acute kidney injury (AKI) refers to a clinical syndrome that occurs as a result of a rapid decline in renal function caused by a variety of etiological factors. AKI is a common complication in critically ill patients, increasing length of hospital stay, hospitalization costs, and morbidity and mortality. In the Intensive Care Unit (ICU), sepsis, cardiac critical illness, hypovolemia, abdominal hypertension, and urinary tract obstruction are among the critical care-related factors that can cause AKI. The pathophysiological mechanisms of AKI are not exactly the same for different critical care etiologies. Altered perfusion is considered an important pathogenesis of AKI, and whether optimization of microcirculation is achieved after optimization of microcirculatory hemodynamics is a blind spot for clinicians. In recent years, contrast-enhanced ultrasound (CEUS) is an emerging imaging technique in the field of critical illness using highly echogenic but inert microbubbles to delineate areas of microvessel perfusion within organs, which has been widely used in oncology and other fields, and for ICU patients, CEUS can quantitatively assess the alterations in renal microcirculatory blood flow. Ultrasound microbubble contrast agent can be injected via peripheral vein through the pulmonary circulation to finally reach the target organ or tissue, to achieve tissue echo enhancement, and the contrast agent can be observed in the tissue of the area of interest. Evaluation of renal microcirculation using ultrasonography allows early detection of people at high risk of AKI, early intervention to avoid the occurrence and development of AKI, and organized and individualized hemodynamic therapy. Therefore, this review discusses the epidemiology of critical illness-related AKI, pathophysiological mechanisms, ultrasonography agents and their techniques, renal ultrasonography procedures and their applications, including the operational steps, renal ultrasonography images at different periods, and the meaning of CEUS parameters. Finally, the current applications of ultrasonography in severe disease-related AKI, especially the evaluation of intrarenal regional blood flow, are summarized.

Epidemiology of acute kidney injury in ICU

Acute kidney injury (AKI), with a prevalence of up to 20–50% and a morbidity and mortality rate of > 10%, increasing the length of hospital stay, hospitalization costs, and morbidity and mortality rates, refers to a clinical syndrome that occurs as a result of a rapid decline in renal function caused by a variety of etiological factors [1,2,3]. There is growing evidence that the burden of AKI extends beyond progression to chronic kidney disease, increased risk of cardiovascular complications, recurrent episodes of AKI, and increased long-term mortality [4]. Due to the complex etiology and specific pathogenesis that remain unclear, there are limited means of clinical assessment and a lack of specific treatments. Treatment to prevent the development or progression of AKI is currently limited to optimizing hemodynamic and fluid status, avoiding nephrotoxins, and the search for a specific pharmacological treatment is hampered by diagnostic delays and complex, incompletely elucidated pathophysiology [5]. Defining the pathophysiological mechanisms of AKI, closely monitoring renal hemodynamics and optimizing the hemodynamic state are essential for the diagnosis and treatment of AKI.

Microcirculation as a key pathogenic mechanism in ICU associated AKI

In the ICU, AKI arises from diverse critical etiologies, each with unique pathophysiologic mechanisms (Fig. 1). Microcirculatory dysfunction, inflammatory dysregulation, and metabolic reorganization are the main causes of renal tubular dysfunction [6]. Alterations in renal perfusion underlie the development of AKI. The kidney has an exceptionally high perfusion rate to maintain a high glomerular filtration rate (GFR). Blood flow enters the kidney through the cortex, with 90% supplied to the cortex, while the medullary blood volume perfuses cortical tissue first, so its proportion is part of the cortical blood volume. The presence of intra-renal shunts makes the medulla more susceptible to hypoxia, and medullary hypoxia resulting from redistribution of intra-renal flow plays an important role in the development of AKI [7,8,9]. Many studies are proving that renal blood flow is increased in the early stage of sepsis, and GFR is decreased due to the abnormal distribution of intrarenal blood flow and the different degree of dilatation of glomerular inlet and outlet arterioles. Whereas sepsis is a dysregulated immune-inflammatory response leading to damage to the vascular endothelium, inappropriate positive fluid balance is central to the further development of sepsis-associated AKI, with dysfunction due to alterations in vascular endothelial cell permeability being the most important pathophysiological mechanism [10, 11]. The kidney serves as an important window for organ perfusion monitoring in ICU patients [12]. Sepsis associated AKI is actually a microcirculatory disease in which inadequate perfusion and hypoxia of renal tissues are emerging as key mediators in the pathogenesis of AKI [13]. Intrarenal hypoxia may result from severely reduced renal blood flow (RBF) and altered intrarenal hemodynamics, for example, renal tubular swelling leading to renal microvascular compression [9]. Using a porcine sepsis induction model, Lima and colleagues demonstrated that renal and subglottic microcirculatory injury persisted after normalization of cardiac output (CO) [14]. Recent studies on post-cardiac surgery patients also link the development of AKI with inadequate renal medullary perfusion and microcirculatory disorders [15]. In severe sepsis, porcine models showed reduced renal cortical microcirculatory blood flow preceding changes in RBF [16]. A rat model similarly demonstrated that during sepsis and septic shock, microcirculatory alterations in peripheral mucosa and kidneys precede overall hemodynamic changes [17].

Fig. 1
figure 1

Diagram of renal hemodynamic mechanisms. a Reduction in mean arterial pressure (MAP) or cardiac output (CO), which determines renal preload, leads to decreased renal blood flow (RBF). This triggers an increase in renal arteriolar resistance (RRI), abnormally high in this context, resulting in a lowered glomerular filtration rate (GFR). This change adversely affects renal microcirculatory blood flow, contributing to AKI. b Increased central venous pressure (CVP), intra-abdominal pressures (IAP), or renal interstitial pressures (IRP) elevate renal venous pressure (RVP). c Discrepancies between renal macrocirculation and microcirculation may arise from various factors, including altered blood viscosity, endothelial dysfunction, increased leukocyte adhesion, glycocalyx degradation, and micro-thrombosis. d Enhanced intrarenal shunting can lead to reduced medullary tissue PO2, causing varying levels of tubular hypoxia. Conversely, a reduction in shunting effectiveness may also induce renal injury via a reactive oxygen species (ROS)-mediated pathway

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The goal of clinical hemodynamic resuscitation is to meet the oxygen and metabolic demands of each organ, which can only be achieved by optimizing the microcirculation [18]. However, studies in patients with septic shock have found that microcirculatory damage is more severe and long-lasting in the kidneys [19]. This shows that there is a difference between macro-circulatory and microcirculatory blood flow, even in different regions [20,21,22]. However, optimization of the macro-circulation may not improve tissue perfusion in the presence of alterations within the microcirculation, including altered blood viscosity, endothelial dysfunction, increased leukocyte adhesion, glycocalyx degradation, and micro-thrombosis [23]. Another risk is the over-optimization of the macro-circulation leads to fluid overload or overuse of vasopressor drugs, which is often deleterious in terms of tissue oxygenation [24]. Clinicians currently pay insufficient attention to organ microcirculation, which prevents them from individualizing resuscitation by targeting the microcirculation.

Abnormal intrarenal shunting is also one of the important hemodynamic mechanisms of acute kidney injury. The kidney’s unique vascular anatomical arrangement facilitates arterio-venous oxygen shunting. This arrangement possibly serves to maintain a stable renal tissue partial pressure of oxygen (PO2) in the presence of variable RBF [25]. However, it can also cause low medullary tissue PO2 when shunting is enhanced, leading to a variable degree of tubular hypoxia. Alternatively, a reduction in shunting effectiveness may also cause renal injury via reactive oxygen species (ROS)-mediated pathway [26, 27]. In a sheep model of septic hyperemic renal dysfunction that reduced medullary blood flow and oxygen tension preceded the decrease in urine output and creatinine clearance [8]. Watchorn et al. demonstrated that the severity of AKI was independent of the degree of renal cortical under-perfusion in patients with septic shock [19]. Treatment with norepinephrine normalized mean arterial pressure (MAP) and increased RBF but further reduced medullary perfusion and oxygenation, and that medullary perfusion appeared to be independent of RBF and cortical perfusion [28]. Renal medullary hypoxia due to redistribution of intrarenal perfusion is thought to be a key mediator of sepsis-related AKI [29].

These findings indicate a mismatch between macrocirculation and microcirculation, the existence of intrarenal shunts, and distinct responses of renal cortical and medullary blood flow under varying conditions. Thus, close monitoring of alterations in renal cortical and medullary microcirculation and a focus on hemodynamic therapy targeting renal microcirculation are vital for diagnosing and treating severe AKI associated with serious illnesses.

The key techniques in assessment of the renal microcirculation

Various methods exist for monitoring renal microcirculation, including invasive laser Doppler, non-invasive imaging techniques, and other imaging modalities that might negatively impact renal function. These approaches, however, are limited by their invasiveness, limited bedside availability, and potential adverse effects on renal function [14, 30,31,32,33]. Previous studies have shown that partial pressure of urine oxygen (PuO2) is closely correlated with medullary oxygen concentration and has been described as a clinical window into renal medullary health [34, 35]. Notably, reduced PuO2 following extracorporeal circulation in cardiac surgery could be associated with the subsequent development of AKI. Improving renal medullary oxygenation during such procedures might attenuate postoperative AKI [36]. However, factors like stagnant urine and low flow rates can influence PuO2 measurements, compromising their ability to accurately reflect renal medullary oxygenation [35, 37]. Therefore, simple and accurate means of monitoring renal microcirculation are needed to guide renal hemodynamic therapy.

Doppler ultrasound, widely recognized as a critical tool in the ICU, is the most common method for clinical evaluation of renal blood flow [38]. CEUS is a technology that can observe organ vascular perfusion in real time, and it can show renal perfusion at different times and in different parts of the kidney [39]. CEUS specifically targets the renal cortex and medulla within the region of interest (ROI), extracting parameters of renal microcirculatory perfusion through a perfusion curve model derived from intensity-over-time data. Its application in studying renal microvascular perfusion is well-documented in both animal models and human subjects. The parameters obtained through CEUS demonstrate strong correlation well with the gold standard measures of renal blood flow, such as para-aminohippurate clearance, in studies involving healthy volunteers [14, 40,41,42,43,44,45]. This method is particularly useful for bedside monitoring of organ microcirculation in patients, providing quantitative assessments of renal perfusion [24, 46,47,48]. CEUS employs ultrasonographic contrast agents consisting of small gas-filled encapsulated microbubbles. Since these microbubbles are confined to the vascular system, CEUS offers a unique approach for visualizing microcirculation and quantifying blood flow. This technique has notable advantages for real time, bedside imaging [49,50,51]. In addition, CEUS’s reproducible characteristics facilitate individualized monitoring of renal microcirculatory perfusion as needed [52]. In various animal studies, CEUS has shown a consistent pattern of renal perfusion enhancement, initially in the renal cortex and subsequently in the medulla. This pattern enables differentiation between cortical and medullary blood flow in kidneys [53,54,55,56]. The safety of CEUS has been established through several large retrospective studies, including those involving critically ill patients [57,58,59].

Microbubble ultrasound contrast agents (UCAs) consist of microbubbles in suspension that interact strongly with the ultrasound beam and are easily detected by ultrasound imaging systems [60]. Currently, great progress has been made in the development of UCAs, mainly in the reduction of the diameter of UCAs (< 8 μm), which allows them to be injected via a peripheral vein through the pulmonary circulation to ultimately reach the target organ or target tissue and achieve tissue echo enhancement, and in the increasing stability of ultrasound microbubble contrast agents, which allows the contrast agent to be observed in the tissue of the region of interest [61]. Presently, the FDA has approved three UCAs for intravascular use: Optison, Definity, and SonoVue [60]. SonoVue is predominantly utilized in Europe [62,63,64]. Excellent contrast agents have the following characteristics: high safety and low side effects; uniform microbubble size with a diameter of less than 10 μm and can be controlled; free passage through capillaries with hemodynamic characteristics similar to those of red blood cells; the ability to generate rich harmonics; and good stability [60]. UCAs are particularly beneficial for patients with compromised renal function as they are non-nephrotoxic and do not induce renal tissue damage [65, 66].

Bedside CEUS enables hemodynamic organization assessment for the treatment of critically ill patients, monitoring renal microcirculatory blood flow dynamically and continuously, and guiding hemodynamic therapy, thus enabling individualized and organized treatment.

Standardized practice and parametric significance of renal CEUS—core prerequisites

Assessment of renal microcirculatory perfusion consists of several parameters [67]. Qontraxt and Sonotumor software analyses the main parameters of time–intensity curve (TIC) of ultrasonography are slightly different (Table 1) [48, 68]. The CEUS parameters correlate with the vascularization of the area analyzed. The time-based variables are more representative of blood flow, whereas the intensity-based variables are suggested to represent blood volume within a specific region. All time and intensity values were calculated from fitted curves rather than from raw image data [50, 69]. For reproducibility studies of CEUS parameters, it was found that in healthy cat kidneys, cortical time parameters had a low coefficient of variation and were reasonably reproducible, whereas intensity parameters and medullary-related parameters were poorly reproducible [70]. In healthy dogs it was also found that time parameters of CEUS had the least variability [71]. Good reproducibility of the parameter mean transit time (MTT) in CEUS assessment of renal cortical perfusion was found in healthy adults [52]. Renal cortical MTT also showed good agreement among different observers [72]. Averkiou et al. compared different software for analyzing contrast TIC and found that rise time (RT) and MTT were reproducible, whereas peak intensity (PI) and area under the curve (AUC) were more variable [73]. There are many factors affecting the results of quantitative analysis of ultrasonography, and the quantitative parameters obtained at different depths are different, and some studies have shown that only the quantitative parameters at the same depth are comparable; meanwhile, the stability of the quantitative parameters obtained at a depth of 4–6 cm is the best; while the size and shape of the ROI have no effect on the quantitative parameters. Different selected sites of the lesion will also affect the results of the analysis of the contrast parameters, thus not accurately reflecting the blood supply of the lesion. Differences in contrast dose and injection rate can significantly affect time to peak (TTP), PI, etc., and therefore factors that may have an impact should be avoided during ultrasonography [74]. The interindividual heterogeneity of CEUS measurements should be attributed to the conditions of acquisition in ICU: renal cortical depth based on the patient's body mass index, respiratory movements that may change the plane of the acquired ultrasound, and changes in tissue thickness and echogenicity over time due to an increase in body fluid balance. of tissue thickness and echogenicity. Such heterogeneity has been reported in previous studies of ICU patients; however, despite this heterogeneity, changes in renal cortical perfusion are readily detectable [47, 75].

Table 1 Main component parameters of TIC
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Standardized ultrasonography procedures and skilled ultrasound techniques are prerequisites for us to obtain accurate data. CEUS uses a dual-image display format with a low mechanical index (MI < 0.1). This format allows two views to be displayed in parallel; the contrast view is constructed by selectively filtering the signal to identify microbubbles while excluding background signals, so that the initial image is blank before contrast is injected. A standard grey-scale image displayed simultaneously identifies the kidney prior to infusion. Low MI ultrasound is necessary to prevent microbubble destruction [48]. Contrast agent use is divided into two methods: infusion and push. In the continuous infusion method, 4.8 ml of SonoVue contrast agent is infused at a rate of 1 ml/min with a special infusion pump until the total amount is infused [76]. The intravenous push method involves a one-time infusion of a certain amount of contrast agent through a central vein (Table 2). It has been found that parameters related to quantitative perfusion by the intravenous push method are reproducible across instruments and analysis software [73]. Different renal ultrasonography images were shown at different times due to the different development times of CEUS in the renal cortex and medulla (Fig. 2). Cortical, medullary and even corticomedullary junction ROIs were sampled (Fig. 3), and since the maximum number of sampling points was 8, 3 ROIs were sampled for cortex and medulla, and 2 ROIs were sampled for corticomedullary junction, with one point at each of the upper, middle and lower poles of the kidneys, respectively, to ensure that they were taken at the same time and to better discriminate between the different parts of the sample.

Table 2 Specific procedures for renal ultrasonography
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Fig. 2
figure 2

a 5–10 s of injected contrast agent microbubbles of contrast agent reached the interlobular arteries and arcuate arteries; b 10–15 s the renal cortex began to develop and gradually enhanced, and the renal medulla did not develop; c renal medulla was developed and gradually enhanced after 25 s; d it began to gradually fade after about 1 min and lasted for about 3–6 min. The above images were derived from our own patients which was approved and agreed the requirement for informed consent by the institutional review board of Peking Union Medical College Hospital (approval number, I-23PJ1284)

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Fig. 3
figure 3

Time–intensity profiles of different sites. a Cortical sampling site and TIC, the screen shows the contrast-enhanced image (C) As well as the conventional ultrasound image (T). b Medullary sampling site and TIC. c Corticomedullary junction sampling site and TIC. d Plotting of regions of interest (ROIs) analyzed by the software, and then generating the supply curves for each ROI (lower section), these curves represent intensity as a function of time. The above images were derived from our own patients which was approved and agreed the requirement for informed consent by the institutional review board of Peking Union Medical College Hospital (approval number, I-23PJ1284)

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Application of CEUS in ICU-related AKI—with emphasis on intrarenal regional blood flow

Normal CEUS renal manifestations

There has been more studies on the application of CEUS (Table 3). As previously discussed, corticomedullary blood flow distribution is uneven, with the medulla receiving less blood supply and being more susceptible to hypoxia [8]. Comprehensive monitoring of intrarenal regional blood flow in different disease states is needed to individually titrate blood pressure targets and find the optimal perfusion pressure to ensure renal perfusion. CEUS has become a crucial technique for bedside assessment of intrarenal regional blood flow in the ICU. This method enables the differentiation of blood flow in the intrarenal cortical, medullary, and corticomedullary junctional zones. This differentiation is possible given the difference in the timing of contrast agent arrival at the cortex and medulla [80]. However, research on the application of CEUS for assessing renal microcirculatory blood flow in ICU patients with AKI exhibits considerable variability. Some studies indicate that CEUS is capable of measuring cortical perfusion, but the assessment of renal medullary blood flow is limited by technical challenges [19]. It has also been shown that there are differences in CEUS measurements of renal cortical and medullary blood flow, and that the changes and significance of blood flow parameters differ between regions. In healthy cats, PI, wash in slope (WIS) and MTT parameters were significantly higher in the renal cortex than in the medulla [54]. In ICU patients, renal cortical TTP parameter and medullary rise time (RT) parameter may contribute to the diagnosis of AKI [81].

Table 3 Apply of CEUS in AKI
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Renal CEUS manifestations in arterial telangiectasia

The renal circulation has two sets of capillary networks, the first being the glomerular capillary network located in the renal cortex, which filters the entire blood volume and forms the second capillary network. The glomerular capillary network is flanked at both ends by small arteries, which result in much higher forward perfusion pressures in the glomerular capillary network than in most other organs, and the kidneys are more susceptible to fluctuations in MAP [82]. In a porcine lipopolysaccharide model showing prolonged alterations in renal microvasculature during shock, CEUS effectively measures dynamic changes in renal microvascular perfusion during shock and resuscitation, insufficient renal microcirculatory perfusion can be quantified by a decrease in peak enhancement, and a decrease in intra-renal blood flow can be measured by measuring microbubble transport between the mesangial arterioles of the renal cortex and the capillaries time is estimated [14]. CEUS detects overall and regional renal perfusion changes induced by systemic hypoxia. Cortical and medullary flow are differentially affected by hypoxia, as evidenced by a significant increase in medullary TTP and MTT parameters and a significant decrease in cortical PI parameter [83].

Renal CEUS manifestations in venous terminal anomalies

The second group of the renal capillary network is the peritubular capillaries located mainly in the medulla, and to reabsorb most of the glomerular filtrate, the pressure within the peritubular capillaries must be sufficiently low. Mildly elevated renal venous pressure leads to increased renin release, resulting in increased renal vascular resistance and decreased renal perfusion [84]. In this case, higher positive perfusion pressure is required to increase renal perfusion, which makes the kidneys more susceptible to fluctuations in MAP and contributes to the onset and progression of AKI [85, 86]. Elevated CVP is the most direct factor affecting RVP and is an independent risk factor for the onset and progression of AKI [87, 88]. For the glomerular microcirculation, there is a curvilinear relationship between CVP and GFR, with GFR first increasing slightly and then decreasing sharply as CVP increases [88]. This subtle increase in GFR may be a reflection of increased cardiac filling to preserve cardiac function by Frank–Starling mechanism (pre-load), and subsequent renal perfusion [89]. While greater CVP levels will then decrease renal perfusion pressure, which will further impair GFR, because an increase in renal venous pressure can cause sodium retention by a direct action on the kidney: a rise in venous pressure could thereby initiate a vicious circle by causing sodium retention, expansion of plasma volume, and further increase in venous pressure [90]. Therefore, different pressures at the refluxing end of the kidney may have different effects on renal cortical and medullary blood flow. It has been shown that in patients with congestive heart failure, baseline TTP is significantly prolonged, and after decongestive therapy, renal cortical TTP decreases but medullary TTP remains unchanged [91]. In a rat model of renal stasis, it was found that renal cortical PI was significantly lower in the CVP 15 mmHg group of rats than in the control group. Whereas, renal medullary PI decreased in rats in CVP 10 mmHg group, but there was no statistical difference [92]. A recent study found that in patients with sepsis, CVP did not correlate with renal venous reflux flatus assessed by Doppler ultrasound, but the severity of renal venous stasis correlated with renal function [93]. In patients with heart failure, baseline renal venous return spectra can be used to predict adverse cardiorenal events [94]. Similarly, Beaubien-Souligny et al. found that venous stasis score, a five-prototypes of venous excess ultrasound (VExUS) grading system, which combines the diameter of the inferior vena cava and the venous Doppler waveforms of the portal, hepatic, and interlobular renal veins, was superior to CVP in identifying venous stasis in patients with post-cardiac AKI [95, 96]. Therefore, identification of renal venous stasis in ICU patients by ultrasound assessment of venous return may be superior to CVP.

CEUS in the prognosis of renal function

CEUS has also been used to assess AKI prognosis, as a new vision for ICU microcirculation, a simplified method for assessing renal perfusion at the bedside, and correlates well with the gold standard renal blood flow measurements [42, 44, 97,98,99,100]. Schneider and colleagues first reported CEUS as a state-of-the-art technique for quantifying tissue perfusion and microcirculation capable of assessing renal cortical perfusion in ICU patients before and after cardiac surgery [75]. Furthermore, significant heterogeneity in renal cortical blood flow exists even in patients with similar degrees of AKI, suggesting that therapeutic interventions should ideally be based on an individual patient basis [19]. The value of CEUS in predicting postoperative renal adverse events has also been demonstrated in patients undergoing colorectal surgery and cardiac surgery [75, 101]. CEUS can be used as a tool for diagnosing the severity of AKI and predicting the renal prognosis of patients with AKI, in which cortical RT can predict AKI stage 3, MTT and RT can predict the initiation of renal replacement therapy (RRT); cortical WIS and medullary RT can predict the recovery of AKI; medullary PI and AUC predicted chronic kidney dysfunction progression; and AUC predicted RRT initiation and AKI recovery [102]. In patients with septic AKI, especially severe AKI, parameters peak time (PT), ascending slope (AS), descending time/2 (DT/2) and MTT are prolonged, and septic patients should be alerted to the possibility of severe AKI when RRI ≥ 0.695 or TTP ≥ 28.4 s [103]. Compared to non-septic shock patients, septic shock patients had a cortical PI parameter was low and MTT parameter was high, and higher in patients with severe AKI; MTT parameter may be a more accurate parameter to assess intrarenal hemodynamics. Similar conclusions have been drawn from comparisons in healthy volunteers versus patients with septic shock [10, 19]. A meta-analysis study demonstrated that reduced microcirculatory perfusion had occurred in AKI patients prior to the alteration of blood creatinine, as evidenced by prolonged perfusion time and reduced of renal cortical AS parameter [104]. TIC in non-AKI patients showed a slowing down after a rapid rise to peak, but AKI patients showed a slow rise to peak followed by a slow decline. The AKI 24-h group exhibited attenuated PI, prolonged PT, and decreased wash-in rate (WIR) compared to the non-AKI 24-h group. Significant differences were also found in day-7 [105]. Renal blood flow and time-averaged velocity were significantly decreased, PI was decreased, and TTP was prolonged between subgroups with exacerbation in the AKI group compared to the non-AKI group. Renal microcirculation PI and TTP parameters were independently and linearly correlated with blood creatinine [106]. The combination of blood creatinine, WIS and PI improved the accuracy of diagnosing septic AKI [107]. About the CEUS parameter relative blood volume (RBV) may be abnormal when renal perfusion reduction is more severe [108].

Application of CEUS in assessing the effects of drugs on the kidney

CEUS has also been used in assessing the effects of drugs on renal microcirculatory blood flow. In patients with septic shock, the CEUS parameter PI was significantly higher in the Terlipressin group than in the control group at 24 h after enrolment. Terlipressin improves renal perfusion in patients with septic shock [109]. Angiotensin II (Ang II) decreases renal cortical PI parameter in humans and the decrease in PI is more pronounced at higher doses, while the opposite is true for Captopril [110]. PI parameter was significantly reduced in healthy populations taking diclofenac sodium [111]. In assessing the role of curcumin in cecum ligation and puncture (CLP) rats, it was found that CEUS parameters PI, DT/2, and AUC were elevated in the curcumin-treated group compared to the CLP group [112]. Dexmedetomidine was found to reduce the incidence of postoperative AKI in non-cardiac postoperative patients [113]. Animal studies have shown that dexmedetomidine significantly improves renal microcirculation in I/R rabbits [114]. Assessment of renal cortical perfusion during I/R in rabbits revealed that AT and TTP values peaked 3 d after I/R surgery and correlated with the most significant pathological changes at the same timepoint [69]. In the I/R cat model, infusion of Ang II resulted in enhanced mean peak renal values, significant decreases in wash-in perfusion index (WiPI) and wash-out rate (WOR), and a trend towards lower wash-in area under the curve (WiAUC) [115]. A porcine model of severe hemodilution found that the use of hydroxyl ethyl starch preserved intrarenal microcirculatory perfusion and renal function [116]. In healthy rabbits, the CEUS parameters TTP and AUC increased significantly while arrival time (AT) and descending time (DT) decreased slightly within 6 h after intramuscular injection of nitroglycerin [117]. The use of hydrocortisone in a dog model resulted in a significant increase in PI parameter in renal cortical and medullary [118].

Clinical application of CEUS and its advantages

CEUS predicts both the occurrence and prognosis of AKI. CEUS assessment suggested that patients at risk of AKI had reduced renal perfusion within 24 h of surgery. Compared with baseline, there was no overall difference in median PI on ICU admission. However, the day after surgery, median PI had decreased by 50%; 48% increase in MTT, both suggestive of decreased perfusion. These differences persisted after correction for hemoglobin; vasopressors use and mean arterial pressure [119]. This suggests to us that monitoring CEUS within 24 h of ICU admission is useful in the clinic. Studies that have also performed continuous CEUS renal monitoring have found that for macro-circulation and other microcirculation indices, renal microcirculation impairment lasted longest (Day 4 was still relevant) [19]. It is meaningful to monitor renal microcirculatory blood flow once a day for 72 h, and comparisons of CEUS parameters still differed between the 120 h groups. Whether assessing renal microcirculatory blood flow with CEUS at times beyond 4 days is meaningful remains to be investigated. Renal microcirculation monitoring in hemodynamically unstable patients still requires individualized monitoring and real-time adjustment of the number and frequency of monitor.

Previous studies have suggested that renal perfusion pressure is determined by MAP–CVP [120]. However, recent study had found that CEUS suggested that renal microcirculatory blood flow was different from macro-circulatory blood flow and other microcirculatory blood flow [19]. CEUS provides a clear picture of blood flow in the renal microcirculation, allows real time, multiple, and as-needed monitoring of the renal microcirculation at the bedside with no renal function side effects, besides, it can distinguish between cortical and medullary blood flow in the kidney. Of course, CEUS still has its problems, the lack of large-scale clinical studies to give international standards, operator differences, patient differences, etc., still need more and more large-scale clinical studies to further confirm.

Renal cortical and medullary blood flow varies in different diseases and CEUS can assist in assessing renal regional blood flow. Renal regional blood flow studies using CEUS in ICU patients are still rare and highly variable. The influence of the arterial and venous ends on the microcirculation and the intricate relationship between them remain unclear. Monitoring intrarenal blood flow, combined with the characteristics of the macro-circulatory hemodynamics is important in the finding the hemodynamic etiology of AKI patients is crucial.

In summary, the assessment and treatment of renal blood flow in patients with severe disease-related AKI is of priority and necessity, and the alteration of renal hemodynamics with microcirculation as the core is the key to the occurrence, development and prognosis of severe disease-related AKI; while microcirculation perfusion in different parts of the kidney is different and should be assessed separately; the comprehensive assessment of renal macro-circulation and microcirculation is important for the clinical adjustment of renal hemodynamic treatment in patients with AKI. CEUS can assess the microcirculation perfusion in different parts of the kidney, is non-invasive, implementable, safe and convenient, and realizes the visualization of bedside renal perfusion imaging, which provides a new method for identifying the high-risk group of AKI as early as possible and avoiding the occurrence and development of AKI, and it is an important means for ICU patients to realize the individualized and organized treatment. At present, CEUS still has its shortcomings, the safety of its application in critically ill patients needs to be further evaluated, and the quantitative analysis is affected by many factors, for which there is no reliable method to overcome, such as tissue harmonic interference, affected by respiratory motion, body mass index, depth, etc., which can only be quantitatively studied in a certain cross section, the dosage and mode of administration of contrast medium, the ultrasound parameter settings, and the significance of the parameters for quantitative analysis. In addition, there is a lack of international standards for quantitative assessment of renal microcirculation with ultrasonography-related data, and large international clinical trials are needed to determine the optimal parameters for clinical assessment and the normal ranges of relevant parameters in different subjects. Therefore, the use of renal ultrasonography for the assessment of renal microcirculation requires strict procedures and careful interpretation of the meaning of the data. More data from CEUS clinical evaluations could provide clinical data to establish appropriate standards.

Availability of data and materials

The data set used and analyzed for the current study is available from the corresponding author on reasonable request.

Abbreviations

AKI:

Acute kidney injury

Ang II:

Angiotensin II

AS:

Ascending slope

AT:

Arrival time

a.u.:

Arbitrary units

AUC:

Area under the curve

CEUS:

Contrast-enhanced ultrasound

CLP:

Cecum ligation and puncture

CO:

Cardiac output

CVP:

Central venous pressure

DS:

Descending slope

DT/2:

Descending time/2

FT:

Fall time

GFR:

Glomerular filtration rate

IAP:

Abdominal pressures

ICU:

Intensive care unit

IRP:

Renal interstitial pressure

MAP:

Mean arterial pressure

MI:

Mechanical index

MTT:

Mean transit time

PE:

Peak enhancement

PI:

Peak intensity

PIT:

Peak intensity time

PT:

Peak time

PO2 :

Pressure of oxygen

PuO2 :

Pressure of urine oxygen

RBF:

Renal blood flow

RBV:

Relative blood volume

ROI:

Region of interest

ROS:

Reactive oxygen species

RRI:

Renal arteriolar resistance

RRT:

Renal replacement therapy

RT:

Rise time

RVP:

Renal venous pressure

TIC:

Time–intensity curve

TTP:

Time to peak

UCA:

Ultrasound contrast agent

WiAUC:

Wash-in area under the curve

WiPI:

Wash-in perfusion index

WIR:

Wash-in rate

WIS:

Wash-in slope

WIT:

Wash-in time

WiWoAUC:

Wash-in and wash-out area under the curve

WoAUC:

Wash-out area under the curve

WOR:

Wash-out rate

WOT:

Wash-out time

References

  1. Section 2: AKI Definition. Kidney Int Suppl. 2012;2(1):19–36.

  2. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411–23.

    Article  PubMed  Google Scholar 

  3. Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, Goldstein SL, Cerda J, Chawla LS. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018;14(10):607–25.

    Article  CAS  PubMed  Google Scholar 

  4. James MT, Bhatt M, Pannu N, Tonelli M. Long-term outcomes of acute kidney injury and strategies for improved care. Nat Rev Nephrol. 2020;16(4):193–205.

    Article  PubMed  Google Scholar 

  5. Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol. 2018;14(4):217–30.

    Article  PubMed  Google Scholar 

  6. Poston JT, Koyner JL. Sepsis associated acute kidney injury. BMJ. 2019;364: k4891.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Evans RG, Ince C, Joles JA, Smith DW, May CN, O’Connor PM, Gardiner BS. Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology. Clin Exp Pharmacol Physiol. 2013;40(2):106–22.

    Article  CAS  PubMed  Google Scholar 

  8. Calzavacca P, Evans RG, Bailey M, Bellomo R, May CN. Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury. Crit Care Med. 2015;43(10):e431-439.

    Article  CAS  PubMed  Google Scholar 

  9. Scholz H, Boivin FJ, Schmidt-Ott KM, Bachmann S, Eckardt KU, Scholl UI, Persson PB. Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection. Nat Rev Nephrol. 2021;17(5):335–49.

    Article  CAS  PubMed  Google Scholar 

  10. Harrois A, Grillot N, Figueiredo S, Duranteau J. Acute kidney injury is associated with a decrease in cortical renal perfusion during septic shock. Crit Care. 2018;22(1):161.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Corradi F, Via G, Tavazzi G. What’s new in ultrasound-based assessment of organ perfusion in the critically ill: expanding the bedside clinical monitoring window for hypoperfusion in shock. Intensive Care Med. 2020;46(4):775–9.

    Article  PubMed  Google Scholar 

  13. Ma S, Evans RG, Iguchi N, Tare M, Parkington HC, Bellomo R, May CN, Lankadeva YR. Sepsis-induced acute kidney injury: a disease of the microcirculation. Microcirculation. 2019;26(2): e12483.

    Article  PubMed  Google Scholar 

  14. Lima A, van Rooij T, Ergin B, Sorelli M, Ince Y, Specht PAC, Mik EG, Bocchi L, Kooiman K, de Jong N, et al. Dynamic contrast-enhanced ultrasound identifies microcirculatory alterations in sepsis-induced acute kidney injury. Crit Care Med. 2018;46(8):1284–92.

    Article  PubMed  Google Scholar 

  15. Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol. 2017;13(11):697–711.

    Article  PubMed  Google Scholar 

  16. Chvojka J, Sykora R, Krouzecky A, Radej J, Varnerova V, Karvunidis T, Hes O, Novak I, Radermacher P, Matejovic M. Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs. Crit Care. 2008;12(6):R164.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hua T, Wu X, Wang W, Li H, Bradley J, Peberdy MA, Ornato JP, Tang W. Micro- and macrocirculatory changes during sepsis and septic shock in a rat model. Shock. 2018;49(5):591–5.

    Article  PubMed  Google Scholar 

  18. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care. 2015;19(Suppl 3):S8.

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  19. Watchorn J, Huang D, Bramham K, Hutchings S. Decreased renal cortical perfusion, independent of changes in renal blood flow and sublingual microcirculatory impairment, is associated with the severity of acute kidney injury in patients with septic shock. Crit Care. 2022;26(1):261.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ospina-Tascon G, Neves AP, Occhipinti G, Donadello K, Büchele G, Simion D, Chierego ML, Silva TO, Fonseca A, Vincent JL, et al. Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med. 2010;36(6):949–55.

    Article  PubMed  Google Scholar 

  21. Pottecher J, Deruddre S, Teboul JL, Georger JF, Laplace C, Benhamou D, Vicaut E, Duranteau J. Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. Intensive Care Med. 2010;36(11):1867–74.

    Article  PubMed  Google Scholar 

  22. Pranskunas A, Koopmans M, Koetsier PM, Pilvinis V, Boerma EC. Microcirculatory blood flow as a tool to select ICU patients eligible for fluid therapy. Intensive Care Med. 2013;39(4):612–9.

    Article  CAS  PubMed  Google Scholar 

  23. Legrand M, Bezemer R, Kandil A, Demirci C, Payen D, Ince C. The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. Intensive Care Med. 2011;37(9):1534–42.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Duranteau J, De Backer D, Donadello K, Shapiro NI, Hutchings SD, Rovas A, Legrand M, Harrois A, Ince C. The future of intensive care: the study of the microcirculation will help to guide our therapies. Crit Care. 2023;27(1):190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Post EH, Kellum JA, Bellomo R, Vincent JL. Renal perfusion in sepsis: from macro- to microcirculation. Kidney Int. 2017;91(1):45–60.

    Article  PubMed  Google Scholar 

  26. Schurek HJ, Jost U, Baumgärtl H, Bertram H, Heckmann U. Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex. Am J Physiol. 1990;259(6 Pt 2):F910-915.

    CAS  PubMed  Google Scholar 

  27. Leong CL, Anderson WP, O’Connor PM, Evans RG. Evidence that renal arterial-venous oxygen shunting contributes to dynamic regulation of renal oxygenation. Am J Physiol Renal Physiol. 2007;292(6):F1726-1733.

    Article  CAS  PubMed  Google Scholar 

  28. Lankadeva YR, Kosaka J, Evans RG, Bailey SR, Bellomo R, May CN. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury. Kidney Int. 2016;90(1):100–8.

    Article  CAS  PubMed  Google Scholar 

  29. Lankadeva YR, Okazaki N, Evans RG, Bellomo R, May CN. Renal medullary hypoxia: a new therapeutic target for septic acute kidney injury? Semin Nephrol. 2019;39(6):543–53.

    Article  CAS  PubMed  Google Scholar 

  30. Lankadeva YR, Kosaka J, Iguchi N, Evans RG, Booth LC, Bellomo R, May CN. Effects of fluid bolus therapy on renal perfusion, oxygenation, and function in early experimental septic kidney injury. Crit Care Med. 2019;47(1):e36–43.

    Article  PubMed  Google Scholar 

  31. Brodman RF, Hackett RL, Finlayson B, Pfaff WW. Microangiography of the renal vasculature following total renal artery occlusion. Surgery. 1974;75(5):734–9.

    CAS  PubMed  Google Scholar 

  32. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18–24.

    Article  PubMed  Google Scholar 

  33. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 1-L infusions of 6% hydroxyethyl starch suspended in 0.9% saline (voluven) and a balanced solution (Plasma Volume Redibag) on blood volume, renal blood flow velocity, and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2014;259(5):881–7.

    Article  PubMed  Google Scholar 

  34. Evans RG, Smith JA, Wright C, Gardiner BS, Smith DW, Cochrane AD. Urinary oxygen tension: a clinical window on the health of the renal medulla? Am J Physiol Regul Integr Comp Physiol. 2014;306(1):R45-50.

    Article  CAS  PubMed  Google Scholar 

  35. Hu RT, Lankadeva YR, Yanase F, Osawa EA, Evans RG, Bellomo R. Continuous bladder urinary oxygen tension as a new tool to monitor medullary oxygenation in the critically ill. Crit Care. 2022;26(1):389.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lankadeva YR, Cochrane AD, Marino B, Iguchi N, Hood SG, Bellomo R, May CN, Evans RG. Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury. Kidney Int. 2019;95(6):1338–46.

    Article  PubMed  Google Scholar 

  37. Silverton NA, Lofgren LR, Hall IE, Stoddard GJ, Melendez NP, Van Tienderen M, Shumway S, Stringer BJ, Kang WS, Lybbert C, et al. Noninvasive urine oxygen monitoring and the risk of acute kidney injury in cardiac surgery. Anesthesiology. 2021;135(3):406–18.

    Article  CAS  PubMed  Google Scholar 

  38. Mayo PH, Chew M, Douflé G, Mekontso-Dessap A, Narasimhan M, Vieillard-Baron A. Machines that save lives in the intensive care unit: the ultrasonography machine. Intensive Care Med. 2022;48(10):1429–38.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wong A, Chew M, Hernandez G. Using ultrasound in ICU. Intensive Care Med. 2023;49(5):563–5.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Fischer K, Meral FC, Zhang Y, Vangel MG, Jolesz FA, Ichimura T, Bonventre JV. High-resolution renal perfusion mapping using contrast-enhanced ultrasonography in ischemia–reperfusion injury monitors changes in renal microperfusion. Kidney Int. 2016;89(6):1388–98.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kogan P, Johnson KA, Feingold S, Garrett N, Guracar I, Arendshorst WJ, Dayton PA. Validation of dynamic contrast-enhanced ultrasound in rodent kidneys as an absolute quantitative method for measuring blood perfusion. Ultrasound Med Biol. 2011;37(6):900–8.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wei K, Le E, Bin JP, Coggins M, Thorpe J, Kaul S. Quantification of renal blood flow with contrast-enhanced ultrasound. J Am Coll Cardiol. 2001;37(4):1135–40.

    Article  CAS  PubMed  Google Scholar 

  43. Wang H, Feng Q, Li C, Zhang H, Peng Y. Ultrasonographic study of hemodynamics and contrast-enhanced ultrasound in the rhesus monkey kidney. Exp Anim. 2022;71(2):116–22.

    Article  CAS  PubMed  Google Scholar 

  44. Hosotani Y, Takahashi N, Kiyomoto H, Ohmori K, Hitomi H, Fujioka H, Aki Y, Fukunaga M, Yuasa S, Mizushige K, et al. A new method for evaluation of split renal cortical blood flow with contrast echography. Hypertens Res. 2002;25(1):77–83.

    Article  PubMed  Google Scholar 

  45. Lüdemann L, Nafz B, Elsner F, Grosse-Siestrup C, Meissler M, Kaufels N, Rehbein H, Persson PB, Michaely HJ, Lengsfeld P, et al. Absolute quantification of regional renal blood flow in swine by dynamic contrast-enhanced magnetic resonance imaging using a blood pool contrast agent. Invest Radiol. 2009;44(3):125–34.

    Article  PubMed  Google Scholar 

  46. Tranquart F, Mercier L, Frinking P, Gaud E, Arditi M. Perfusion quantification in contrast-enhanced ultrasound (CEUS)-ready for research projects and routine clinical use. Ultraschall Med. 2012;33(Suppl 1):S31-38.

    PubMed  Google Scholar 

  47. Schneider AG, Goodwin MD, Schelleman A, Bailey M, Johnson L, Bellomo R. Contrast-enhanced ultrasonography to evaluate changes in renal cortical microcirculation induced by noradrenaline: a pilot study. Crit Care. 2014;18(6):653.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Arditi M, Frinking PJ, Zhou X, Rognin NG. A new formalism for the quantification of tissue perfusion by the destruction-replenishment method in contrast ultrasound imaging. IEEE Trans Ultrason Ferroelectr Freq Control. 2006;53(6):1118–29.

    Article  PubMed  Google Scholar 

  49. Hoeffel C, Mulé S, Huwart L, Frouin F, Jais JP, Helenon O, Correas JM. Renal blood flow quantification in pigs using contrast-enhanced ultrasound: an ex vivo study. Ultraschall Med. 2010;31(4):363–9.

    Article  CAS  PubMed  Google Scholar 

  50. Dietrich CF, Averkiou MA, Correas JM, Lassau N, Leen E, Piscaglia F. An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion. Ultraschall Med. 2012;33(4):344–51.

    Article  CAS  PubMed  Google Scholar 

  51. Greis C. Ultrasound contrast agents as markers of vascularity and microcirculation. Clin Hemorheol Microcirc. 2009;43(1–2):1–9.

    Article  PubMed  Google Scholar 

  52. Almushayt SJ, Pham A, Phillips BE, Williams JP, Taal MW, Selby NM. Repeatability of contrast-enhanced ultrasound to determine renal cortical perfusion. Diagnostics (Basel). 2022;12(5):1293.

    Article  PubMed  Google Scholar 

  53. Macrì F, Di Pietro S, Liotta L, Piccionello AP, Pugliese M, De Majo M. Effects of size and location of regions of interest examined by use of contrast-enhanced ultrasonography on renal perfusion variables of dogs. Am J Vet Res. 2016;77(8):869–76.

    Article  PubMed  Google Scholar 

  54. Schweiger H, Ohlerth S, Gerber B. Contrast-enhanced ultrasound of both kidneys in healthy, non-anaesthetized cats. Acta Vet Scand. 2015;57:80.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yi K, Ji S, Kim J, Yoon J, Choi M. Contrast-enhanced ultrasound analysis of renal perfusion in normal micropigs. J Vet Sci. 2012;13(3):311–4.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Mahoney M, Sorace A, Warram J, Samuel S, Hoyt K. Volumetric contrast-enhanced ultrasound imaging of renal perfusion. J Ultrasound Med. 2014;33(8):1427–37.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol. 2008;102(12):1742–6.

    Article  PubMed  Google Scholar 

  58. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol. 2008;51(17):1704–6.

    Article  PubMed  Google Scholar 

  59. Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, Wilson S, Fane L, Herzog CA, Zoghbi WA, et al. The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr. 2008;21(11):1202–6.

    Article  PubMed  Google Scholar 

  60. Chong WK, Papadopoulou V, Dayton PA. Imaging with ultrasound contrast agents: current status and future. Abdom Radiol (NY). 2018;43(4):762–72.

    Article  PubMed  Google Scholar 

  61. Morel DR, Schwieger I, Hohn L, Terrettaz J, Llull JB, Cornioley YA, Schneider M. Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging. Invest Radiol. 2000;35(1):80–5.

    Article  CAS  PubMed  Google Scholar 

  62. Claudon M, Dietrich CF, Choi BI, Cosgrove DO, Kudo M, Nolsoe CP, Piscaglia F, Wilson SR, Barr RG, Chammas MC, et al. Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver—update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound Med Biol. 2013;39(2):187–210.

    Article  PubMed  Google Scholar 

  63. Piscaglia F, Nolsoe C, Dietrich CF, Cosgrove DO, Gilja OH, Bachmann Nielsen M, Albrecht T, Barozzi L, Bertolotto M, Catalano O, et al. The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall Med. 2012;33(1):33–59.

    Article  CAS  PubMed  Google Scholar 

  64. D’Onofrio M, Romanini L, Serra C, Magnolfi F, Bertolotto M, Quaia E, Puntel G, Colleoni A, Fiorini E, Cenci C, et al. Contrast enhancement ultrasound application in focal liver lesions characterization: a retrospective study about guidelines application (SOCEUS-CEUS survey). J Ultrasound. 2016;19(2):99–106.

    Article  PubMed  Google Scholar 

  65. Correas JM, Anglicheau D, Joly D, Gennisson JL, Tanter M, Hélénon O. Ultrasound-based imaging methods of the kidney-recent developments. Kidney Int. 2016;90(6):1199–210.

    Article  PubMed  Google Scholar 

  66. Jiménez C, de Gracia R, Aguilera A, Alonso S, Cirugeda A, Benito J, Regojo RM, Aguilar R, Warlters A, Gómez R, et al. In situ kidney insonation with microbubble contrast agents does not cause renal tissue damage in a porcine model. J Ultrasound Med. 2008;27(11):1607–15.

    Article  PubMed  Google Scholar 

  67. Kalantarinia K, Belcik JT, Patrie JT, Wei K. Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound. Am J Physiol Renal Physiol. 2009;297(4):F1129-1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ma F, Cang Y, Zhao B, Liu Y, Wang C, Liu B, Wu T, Song Y, Peng A. Contrast-enhanced ultrasound with SonoVue could accurately assess the renal microvascular perfusion in diabetic kidney damage. Nephrol Dial Transplant. 2012;27(7):2891–8.

    Article  PubMed  Google Scholar 

  69. Luo Z, Liu Y, Tang Z, Liu J, Xu X, Li M, Dai Y. Quantitative evaluation of renal cortex perfusion using contrast-enhanced ultrasound imaging parameters in ischemia-reperfusion injury in rabbits. Ultrasound Med Biol. 2021;47(11):3253–62.

    Article  PubMed  Google Scholar 

  70. Stock E, Duchateau L, Saunders JH, Volckaert V, Polis I, Vanderperren K. Repeatability of contrast-enhanced ultrasonography of the kidneys in healthy cats. Ultrasound Med Biol. 2018;44(2):426–33.

    Article  PubMed  Google Scholar 

  71. Liu DJX, Hesta M, Stock E, Bogaerts E, Broeckx BJG, Saunders JH, Vanderperren K. Renal perfusion parameters measured by contrast-enhanced ultrasound in healthy dogs demonstrate a wide range of variability in the long-term. Vet Radiol Ultrasound. 2019;60(2):201–9.

    Article  PubMed  Google Scholar 

  72. Hillaert A, Stock E, Favril S, Duchateau L, Saunders JH, Vanderperren K. Intra- and inter-observer variability of quantitative parameters used in contrast-enhanced ultrasound of kidneys of healthy cats. Animals (Basel). 2022;12(24):3557.

    Article  PubMed  Google Scholar 

  73. Averkiou MA, Juang EK, Gallagher MK, Cuevas MA, Wilson SR, Barr RG, Carson PL. Evaluation of the reproducibility of bolus transit quantification with contrast-enhanced ultrasound across multiple scanners and analysis software packages—a quantitative imaging biomarker alliance study. Invest Radiol. 2020;55(10):643–56.

    Article  CAS  PubMed  Google Scholar 

  74. Ignee A, Jedrejczyk M, Schuessler G, Jakubowski W, Dietrich CF. Quantitative contrast enhanced ultrasound of the liver for time intensity curves-reliability and potential sources of errors. Eur J Radiol. 2010;73(1):153–8.

    Article  PubMed  Google Scholar 

  75. Schneider AG, Goodwin MD, Schelleman A, Bailey M, Johnson L, Bellomo R. Contrast-enhanced ultrasound to evaluate changes in renal cortical perfusion around cardiac surgery: a pilot study. Crit Care. 2013;17(4):R138.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Schneider A, Johnson L, Goodwin M, Schelleman A, Bellomo R. Bench-to-bedside review: contrast enhanced ultrasonography—a promising technique to assess renal perfusion in the ICU. Crit Care. 2011;15(3):157.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Seo N, Oh H, Oh HJ, Chung YE. Quantitative analysis of microperfusion in contrast-induced nephropathy using contrast-enhanced ultrasound: an animal study. Korean J Radiol. 2021;22(5):801–10.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Liu DJX, Stock E, Broeckx BJG, Daminet S, Meyer E, Delanghe JR, Croubels S, Devreese M, Nguyen P, Bogaerts E, et al. Weight-gain induced changes in renal perfusion assessed by contrast-enhanced ultrasound precede increases in urinary protein excretion suggestive of glomerular and tubular injury and normalize after weight-loss in dogs. PLoS ONE. 2020;15(4): e0231662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nylund K, Sævik F, Leh S, Pfeffer F, Hausken T, Gilja OH. Interobserver analysis of CEUS-derived perfusion in fibrotic and inflammatory Crohn’s disease. Ultraschall Med. 2019;40(1):76–84.

    Article  PubMed  Google Scholar 

  80. Xie JG, Zeng P, Xiao WX, Bin JP, Liu YL. Experimental study of the characteristics of renal blood flow with contrast ultrasound. Di Yi Jun Yi Da Xue Xue Bao. 2005;25(8):1040–2.

    PubMed  Google Scholar 

  81. Song Y, Mei J, Xu D, Ma Y. Evaluation of contrast-enhanced ultrasound in diagnosis of acute kidney injury of patients in intensive care unit. Int J Gen Med. 2023;16:2229–36.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583–93.

    Article  CAS  PubMed  Google Scholar 

  83. Brabrand K, de Lange C, Emblem KE, Reinholt FP, Saugstad OD, Stokke ES, Munkeby BH. Contrast-enhanced ultrasound identifies reduced overall and regional renal perfusion during global hypoxia in piglets. Invest Radiol. 2014;49(8):540–6.

    Article  CAS  PubMed  Google Scholar 

  84. Kishimoto T, Maekawa M, Abe Y, Yamamoto K. Intrarenal distribution of blood flow and renin release during renal venous pressure elevation. Kidney Int. 1973;4(4):259–66.

    Article  CAS  PubMed  Google Scholar 

  85. Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 2019;96(5):1083–99.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Chen KP, Cavender S, Lee J, Feng M, Mark RG, Celi LA, Mukamal KJ, Danziger J. Peripheral edema, central venous pressure, and risk of AKI in critical illness. Clin J Am Soc Nephrol. 2016;11(4):602–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Legrand M, Dupuis C, Simon C, Gayat E, Mateo J, Lukaszewicz AC, Payen D. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care. 2013;17(6):R278.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009;53(7):582–8.

    Article  PubMed  Google Scholar 

  89. Guyton AC, Jones CE. Central venous pressure: physiological significance and clinical implications. Am Heart J. 1973;86(4):431–7.

    Article  CAS  PubMed  Google Scholar 

  90. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet. 1988;1(8593):1033–5.

    Article  CAS  PubMed  Google Scholar 

  91. Komuro K, Shimazu K, Koizumi T, Imagawa S, Anzai T, Yonezawa K. Demonstration of improved renal congestion after heart failure treatment on renal perfusion imaging with contrast-enhanced ultrasonography. Circ Rep. 2019;1(12):593–600.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Komuro K, Seo Y, Yamamoto M, Sai S, Ishizu T, Shimazu K, Takahashi Y, Imagawa S, Anzai T, Yonezawa K, et al. Assessment of renal perfusion impairment in a rat model of acute renal congestion using contrast-enhanced ultrasonography. Heart Vessels. 2018;33(4):434–40.

    Article  PubMed  Google Scholar 

  93. Fujii K, Nakayama I, Izawa J, Iida N, Seo Y, Yamamoto M, Uenishi N, Terasawa T, Iwata M. Association between intrarenal venous flow from Doppler ultrasonography and acute kidney injury in patients with sepsis in critical care: a prospective, exploratory observational study. Crit Care. 2023;27(1):278.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Husain-Syed F, Singam NSV, Viehman JK, Vaughan L, Bauer P, Gall H, Tello K, Richter MJ, Yogeswaran A, Romero-González G, et al. Changes in Doppler-derived kidney venous flow and adverse cardiorenal outcomes in patients with heart failure. J Am Heart Assoc. 2023;12(16): e030145.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Beaubien-Souligny W, Rola P, Haycock K, Bouchard J, Lamarche Y, Spiegel R, Denault AY. Quantifying systemic congestion with Point-Of-Care ultrasound: development of the venous excess ultrasound grading system. Ultrasound J. 2020;12(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Beaubien-Souligny W, Benkreira A, Robillard P, Bouabdallaoui N, Chassé M, Desjardins G, Lamarche Y, White M, Bouchard J, Denault A. Alterations in portal vein flow and intrarenal venous flow are associated with acute kidney injury after cardiac surgery: a prospective observational cohort study. J Am Heart Assoc. 2018;7(19): e009961.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Göcze I, Renner P, Graf BM, Schlitt HJ, Bein T, Pfister K. Simplified approach for the assessment of kidney perfusion and acute kidney injury at the bedside using contrast-enhanced ultrasound. Intensive Care Med. 2015;41(2):362–3.

    Article  PubMed  Google Scholar 

  98. Harrois A, Duranteau J. Contrast-enhanced ultrasound: a new vision of microcirculation in the intensive care unit. Crit Care. 2013;17(4):449.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jun W, Chen DC. Contrast-enhanced ultrasonography: a promising method for blood flow and perfusion evaluation in critically ill patients. Chinese Med J. 2018;131(10):1135.

    Article  Google Scholar 

  100. Wu J, Chen DC. Contrast-enhanced ultrasonography: a promising method for blood flow and perfusion evaluation in critically ill patients. Chin Med J (Engl). 2018;131(10):1135–7.

    Article  PubMed  Google Scholar 

  101. Read DJ, Doleman B, Heinink T, Selby NM, Lund JN, Phillips BE, Williams JP. Contrast-enhanced ultrasound assessed renal microvascular perfusion may predict postoperative renal complications following colorectal surgery. Clin Exp Pharmacol Physiol. 2021;48(7):971–7.

    Article  CAS  PubMed  Google Scholar 

  102. Yoon HE, Kim DW, Kim D, Kim Y, Shin SJ, Shin YR. A pilot trial to evaluate the clinical usefulness of contrast-enhanced ultrasound in predicting renal outcomes in patients with acute kidney injury. PLoS ONE. 2020;15(6): e0235130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liu P, Cai X, Zhang Y, Li Y, Liu L. The clinical application of ultrasound for acute kidney injury during sepsis-from macroscopic to microscopic renal perfusion perspectives. Ultrasound Med Biol. 2023;49:2017.

    Article  PubMed  Google Scholar 

  104. Li Y, Chen L, Feng L, Li M. Contrast-enhanced ultrasonography for acute kidney injury: a systematic review and meta-analysis. Ultrasound Med Biol. 2023;49:1930.

    Article  PubMed  Google Scholar 

  105. Wang J, Gao X, Wang D, Wang Z, Li Z, Liu D, Xu L. Continuous contrast-enhanced ultrasound applied to acute kidney injury caused by sepsis: a diagnostic clinical study. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2018;30(2):160–4.

    PubMed  Google Scholar 

  106. Liu PQ, Ding CW, Zhang YC, Ma Q, Liu LJ. Diagnostic value of ultrasound and contrast-enhanced ultrasound in septic acute kidney injury. J Clin Ultrasound. 2022;50(4):505–14.

    Article  PubMed  Google Scholar 

  107. Wang XY, Pang YP, Jiang T, Wang S, Li JT, Shi BM, Yu C. Value of early diagnosis of sepsis complicated with acute kidney injury by renal contrast-enhanced ultrasound. World J Clin Cases. 2019;7(23):3934–44.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ince C, Boerma EC, Cecconi M, De Backer D, Shapiro NI, Duranteau J, Pinsky MR, Artigas A, Teboul JL, Reiss IKM, et al. Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2018;44(3):281–99.

    Article  PubMed  Google Scholar 

  109. Wang J, Shi M, Huang L, Li Q, Meng S, Xu J, Xue M, Xie J, Liu S, Huang Y. Addition of terlipressin to norepinephrine in septic shock and effect of renal perfusion: a pilot study. Renal Fail. 2022;44(1):1207–15.

    Article  CAS  Google Scholar 

  110. Schneider AG, Hofmann L, Wuerzner G, Glatz N, Maillard M, Meuwly JY, Eggimann P, Burnier M, Vogt B. Renal perfusion evaluation with contrast-enhanced ultrasonography. Nephrol Dial Transplant. 2012;27(2):674–81.

    Article  CAS  PubMed  Google Scholar 

  111. Imamura H, Hata J, Iida A, Manabe N, Haruma K. Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study. Eur J Clin Pharmacol. 2013;69(2):161–5.

    Article  CAS  PubMed  Google Scholar 

  112. Wang S, Zhao P, Zhang Y, Zhu L, Zhu J, Luo Y, Li Q. The therapeutic effects of curcumin in early septic acute kidney injury: an experimental study. Drug Des Devel Ther. 2021;15:4243–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tang YZ, Wang Q, Zhi L, Liu X, Le Y, Liao Q, Li B, Zhang W. Intraoperative dexmedetomidine use is associated with lower incidence of acute kidney injury after non-cardiac surgery. Ren Fail. 2023;45(1):2192285.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Si YN, Han L, Zhang Y, Chen LH, Xu YJ, Sun F, Pan XX, Zeng LQ, Bao HG. Effects of dexmedetomidine on microcirculatory perfusion in rabbits with renal ischemia/reperfusion injury: quantitative evaluation with contrast-enhanced ultrasound. Nan Fang Yi Ke Da Xue Xue Bao. 2016;36(5):628–32.

    CAS  PubMed  Google Scholar 

  115. Stock E, Vanderperren K, Bosmans T, Dobbeleir A, Duchateau L, Hesta M, Lybaert L, Peremans K, Vandermeulen E, Saunders J. Evaluation of feline renal perfusion with contrast-enhanced ultrasonography and scintigraphy. PLoS ONE. 2016;11(10): e0164488.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Ergin B, van Rooij T, Lima A, Ince Y, Specht PAC, Mik EG, Kooiman K, de Jong N, Ince C. Hydroxyl ethyl starch (HES) preserves intrarenal microcirculatory perfusion shown by contrast-enhanced ultrasound (Ceus), and renal function in a severe hemodilution model in pigs. Shock. 2022;57(3):457–66.

    Article  CAS  PubMed  Google Scholar 

  117. Dong Y, Wang WP, Cao JY, Fan PL, Lin XY. Quantitative evaluation of acute renal failure in rabbits with contrast-enhanced ultrasound. Chin Med J (Engl). 2012;125(4):652–6.

    PubMed  Google Scholar 

  118. Haers H, Daminet S, Smets PM, Duchateau L, Aresu L, Saunders JH. Use of quantitative contrast-enhanced ultrasonography to detect diffuse renal changes in Beagles with iatrogenic hypercortisolism. Am J Vet Res. 2013;74(1):70–7.

    Article  PubMed  Google Scholar 

  119. Harrois A, Duranteau J. Contrast-enhanced ultrasound: a new vision of microcirculation in the intensive care unit. Crit Care. 2013;17:449.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Dang PT, Lopez BE, Togashi K. A decrease in effective renal perfusion pressure is associated with increased acute kidney injury in patients undergoing cardiac surgery. Cureus. 2023;15(9): e45036.

    PubMed  PubMed Central  Google Scholar 

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Funding

Thanks to the Beijing Municipal Science and Technology Commission for the financial support (No. Z201100005520038) and the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-A-218).

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Authors and Affiliations

  1. Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

    Rongping Chen, Beijun Gao, Xinchen Wang, Hua Zhao, Xiaoting Wang & Dawei Liu

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  1. Rongping Chen
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  2. Beijun Gao
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  3. Xinchen Wang
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  4. Hua Zhao
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  5. Xiaoting Wang
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Contributions

RPC, HZ, XTW and DWL discussed and performed the study. RPC wrote the main manuscript, prepared figures and tables. BJG and XCW helped to give suggestions for figures. HZ, XTW and DWL revised the manuscript. All authors read, critically reviewed, and approved the final manuscript. HZ takes responsibility for the paper as a whole. All authors read and approved the final manuscript.

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Correspondence to Hua Zhao, Xiaoting Wang or Dawei Liu.

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Chen, R., Gao, B., Wang, X. et al. Ultrasonographic assessment of renal microcirculation is a new vision for the treatment of intensive care unit associated acute kidney injury. Eur J Med Res 29, 115 (2024). https://doi.org/10.1186/s40001-024-01704-y

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Keywords

European Journal of Medical Research

ISSN: 2047-783X

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