The Characteristics of Renal Microperfusion in Acute Kidney Injury: Initial Experience with Quantitative Contrast-Enhanced Ultrasound

doi:10.21203/rs.3.rs-4280366/v1

This study aimed to assess use of contrast-enhanced ultrasonography (CEUS) in evaluating patients with acute kidney injury (AKI) and investigate its correlationwith renal pathology and clinical outcomes. 16 patients with AKI induced by tubulointerstitial nephritis and 12 volunteers. CEUS parameters, including peak intensity (PI), rise time (RT), time to peak (TTP), mean transit time (mTT), and their cortex-to-medulla ratio, were compared within AKI subgroups and the control group. The relationship of these parameters with renal pathology and renal outcome was analyzed.

The cortex-to-medulla PI ratio of AKI showed a decrease, indicating the presence of medullary congestion. In patients with AKI stage 3, the cortex-to-medulla PI ratio showed positive correlation with the glomerular sclerosis score(r=0.690). Additionally, the score for chronic tubulointerstitial injury had negative correlations with cortical RT and cortical TTP (r=-0.807 and r=-0.821), and their cortex-to-medulla ratios (r=-0.576 and r=-0.547), while having a positive correlation with cortex-to-medulla PI ratio (r=-0.501). 14 patients underwent a 3-month follow-up. Subsequent comparison disclosed that a lower PI ratio was closely related to a more favorable renal outcome.

We found CEUS enables the detection of renal perfusion redistribution in AKI, and a reduced cortex-to-medulla PI ratio suggests medullary congestion. The cortex-to-medulla PI ratio holds potential as a prognostic indicator for AKI, contributing to both diagnosis and the prediction of renal outcomes.

Health sciences/Medical research

Health sciences/Nephrology

acute kidney injury

contrast-enhanced ultrasonography

cortex-to-medulla ratio

peak intensity

tubulointerstitial nephritis

Acute kidney injury (AKI) is a condition where kidney function deteriorates rapidly within a few hours to days¹. It is strongly linked with mortality². Kidney damage can be caused by factors like kidney ischemia, exposure to nephrotoxins, or sepsis. AKI is considered a microcirculation disease, and disturbances in intrarenal microcirculation and tissue oxygenation are currently believed to be essential mechanisms behind its onset and progression³ ^4-6. Studies on ischemic AKI have shown a redistribution of intrarenal perfusion in the cortex and medulla, along with a loss of renal peritubular microvasculature. Inadequate restoration of peritubular capillary density and delayed recovery of tubules following the initial injury are proposed mechanism for the progression of AKI to chronic kidney disease (CKD) ⁷. Studies on ischemic AKI have shown a redistribution of intrarenal perfusion in the cortex and medulla, along with a loss of renal peritubular microvasculature^8,9. Unfortunately, non-invasive imaging techniques that allow for the precise and quantitative evaluation of renal microperfusion are currently lacking.

Several functional imaging technologies, such as magnetic resonance imaging (MRI) and contrast-based ultrasonography, have been employed in preclinical studies to predict and monitor the progression of kidney disease⁷. These studies have demonstrated that quantitative parameters obtained from diffusion-weighted imaging (DWI), diffusion tensor imaging(DTI), and blood oxygen level-dependent MRI can be used to assess alterations in renal microstructure and function^10-13. However, the clinical application of MRI in humans has limitations. It requires long imaging times, making it less suitable for critically ill patients during their stay in the intensive care unit (ICU). The use of gadolinium-based contrast agents, common in MRI, risks nephrogenic systemic fibrosis and contraindicated in those with kidney impairment. Additionally, MRI systems are bulky, immobile, and expensive, impractical for critically ill ICU patients.

Ultrasound imaging offers several advantages for clinical applications, including its repeatability, portability, and lack of hepatorenal toxicity. Color Doppler ultrasound can evaluate changes in renal blood flow, but it only provides indirect measurements of microvascular parameters. In contrast, CEUS enables sensitive and quantitative assessment of kidney microperfusion at the bedside¹⁴. CEUS relies on the use of tiny gas-filled microbubbles that are similar in size to red blood cells as contrast agents¹⁵. These microbubbles are eliminated through the pulmonary route, minimizing the potential harm to liver and kidney function. Compared to CT and MRI, CEUS offers higher resolution, real-time dynamic response, and improved visualization of vascular morphology in hepatic diseases. CEUS holds promise as a valuable tool for clinical applications. However, there is limited evidence regarding the utilization of CEUS in patients with AKI.

In this study, we aimed to combine CEUS imaging with conventional and elastography ultrasonography in evaluating microperfusion in patients with AKI. Our objective was to quantitatively assess microcirculation and clinicopathological disease activity and determine its predictive value for renal outcome.

Demographics and Baseline Characteristics

A total of 21 patients were initially recruited for the study. However, five patients were excluded for various reasons. One patient had a large cyst in the right kidney, another had renal cortical necrosis, and a third had significant interstitial fibrosis involving over 50% of the interstitial area. Two additional patients were excluded due to unsatisfactory contrast images. One patient had an image obscured by ribs, and another patient had a contrast perfusion time of less than 3 minutes. As a result, the statistical analysis included 16 patients with AKI. The baseline characteristics of these patients are summarized in Supplementary Table 1.

Characteristics of CEUS and other Ultrasonic Parameters

In Table 1, the CEUS-derived PI, RT, TTP, mTT, and their cortex-to-medulla ratios were compared within the subgroups of AKI patients and healthy controls. The results showed that in patients with mild injury (eGFR >25 ml/min/1.73 m²), blood flow responded to distribute more in the medulla, leading to medullary congestion and a cortex-to-medulla PI ratio of less than one (0.80±0.24). The AKI patients also showed a decreasing trend in both cortical and medullary mTTs compared to the control group, although statistical significance was not observed. The SWV obtained through p-SWE of AKI patients decreased as eGFR declined, the difference observed at the onset between patients with eGFR >25 ml/min/1.73 m²and those with eGFR <25 ml/min/1.73 m² was significant. The RI of both the main renal artery and segmental artery, determined through color Doppler ultrasound imaging, increased significantly as renal function deteriorated.

Correlation analysis of ultrasonic parameters with renal pathology and different renal outcomes

The associations between ultrasonography-derived parameters and renal pathology were assessed (show in Supplementary Tables 2-4). No strong correlations were found between the ultrasonic parameters and pathological scores for GS and active TI injuries. However, in patients with AKI stage 3, the cortex-to-medulla PI ratio was positively correlated with the glomerulosclerosis (GS) scores (r=0.690, p=0.03), the RI of renal main artery showed a positive correlation with the score for active TI injury (r=0.717, p=0.02). Additionally, the score for chronic TI injury was found to have negative correlations with cortical RT, cortical TTP and RI of renal segmental artery (r=-0.807, r=-0.821 and r=-0.499, respectively), and the cortex-to-medulla ratios of RT and TTP (r=-0.576 and r=-0.547, respectively), while having a positive correlation with cortex-to-medulla PI ratio (r=-0.501, p=0.05). All these findings supported the obvious redistribution of perfusion in the cortex and medulla in patients with AKI. The close relationship found between chronic TI score and cortex-to-medulla ratios of PI, RT and TTP, might indicate varied potential regulation capabilities of individuals to AKI.

A subgroup analysis was conducted on a subset of 14 patients who underwent a 3-month follow-up. Most of these patients showed a significant recovery of renal function. After three months of follow-up, 9 patients had eGFRs ≥45 mL/min/1.73 m², 3 patients had eGFRs of 15-45 mL/min/1.73 m², and 2 patients had their eGFRs ≤15 ml/min/1.73 m² (14.3%). Subsequent comparison disclosed that a lower PI ratio was closely related to a more favorable renal outcome (p=0.02) (show in SupplementaryTable 5).

Our study population consisted of patients with pathologically confirmed AKI. In addition to using ultrasonography and elastography, we utilized CEUS to evaluate the microvascular perfusion of the kidneys. Our findings demonstrated a significant decrease in the cortex-to-medulla ratio peak of intensity in AKI patients, indicating a redistribution of intrarenal microcirculation that favored the medulla ^16,17, but without significant changes of PIs^1,18. This finding contrasts with previous literature which reported a decrease in microvascular perfusion in either the cortex or the medulla. In line with other studies, our results suggest that patients with AKI experience medullary hyperemia, evident in an increased medullary area under the curve. One possible mechanism for this change was the adaptive response of the kidneys to systemic inflammation minimizing exposure to reactive oxygen species thereby reducing blood volume in the cortex. The microvascular endothelial cells were diffusely involved and damaged by inflammatory mediators, increasing resistance (reflected by increased RI of renal arteries in this study), permeability and resulting in contraction of microcirculation, further reducing cortical blood perfusion. The strong correlation observed between the cortex-to-medulla PI ratio and the improvement in renal recovery highlights the significance of the PI ratio in assessing renal outcomes. However, owing to the limited sample size, further investigation is necessary to validate the superiority of the PI ratio.

The CEUS-derived mTT represents the average duration of blood flow that passes through the capillary network. In our study, we observed a decrease in both cortical and medullary mTTs, indicating a reduction in effective circulating blood volume. This decline may be attributed to a decrease in functional glomeruli, leading to inefficient completion of the circulatory process. Rise time was used to measure the blood flow speed and renal parenchymal resistance, whereas TTP was used to assess the average duration of blood flow to traverse the capillary network. A study on diabetic kidney disease demonstrated that glomerular nodular or diffuse sclerosis directly leads to a notable reduction in renal perfusion¹⁹, and most perfusion parameters showed a negative correlation with glomerulosclerosis, while falling time, a time-dependent parameter indicating renal clearance, showed a positive correlation. In our study on AKI stage 3 patients, we observed negative correlations between the degree of chronic TI injury and the cortical TTP and RT in AKI stage 3. We postulated that as AKI progresses, the extent of TI injury worsens, resulting in impaired function of the peritubular capillary network. This impairment affects the effective circulation of renal plasma flow, leading to truncation of blood flow in the capillary network. In addition, intrinsic AKI, such as acute tubular injury and tubulointerstitial nephritis, can activate tubuloglomerular feedback mechanisms, leading to a decrease in glomerular filtration rate. The activated tubular cells release vasoactive mediators and pro-inflammatory cytokines, causing vasoconstriction in arterioles and contraction of mesangial cells, ultimately reducing the ultrafiltration coefficient. These processes collectively contribute to the decline in GFR, which consequently results in a shortened TTP²⁰. In addition, the close relationship between chronic TI score and cortex-to-medulla ratios of PI, RT and TTP, might indicate varied potential regulation capabilities of individuals to AKI, therefore influencing on the recovery of renal function.

Previous studies have suggested that RI could be a useful tool for the early identification of AKI and its potential reversibility in critically ill patients^21-23. Our study revealed a positive link between the RI of the renal and segmental arteries and the severity of active interstitial inflammation and edema. These changes in blood flow are likely caused by damage to the renal tubular epithelial cells, which often swell, shed, accumulate debris, and undergo localized necrosis due to inflammatory reactions. This results in edema in the renal tubular interstitium, compressing small blood vessels, increasing vascular resistance, and causing microvascular stasis¹⁹. However, the utility of RI for monitoring renal perfusion remains uncertain because of the influence of multiple factors like vascular compliance, vascular resistance, as well as pathological factors such as interstitial pressure and intra-abdominal pressure. Therefore, the ability of RI to accurately reflect renal perfusion and function remains a topic of debate and requires further investigation²⁴. In addition, there was an inverse correlation between the pathological scores of active interstitial lesions and SWV. Decreased tissue perfusion and interstitial edema may result in this decrease in p-SWE²⁵.

This study has several limitations, mainly related to the relatively small sample size. Thus, this study may lack sufficient statistical power to accurately predict the prognosis of AKI and can only offer a directional trend as a reference. Future large-scale studies with larger sample sizes and extended follow-up periods are required to further explore the potential diagnostic and prognostic values of these parameters.

Study design and patients

This prospective cohort study included patients with AKI. The study subjects were enrolled from Peking University First Hospital between August 2022 and February 2023. AKI was diagnosed and staged into subgroups based on serum creatinine following the Kidney Disease Improving Global Outcomes (KDIGO)²⁶. The study included patients who were pathologically diagnosed with tubulointerstitial nephritis and had successfully completed the series of ultrasound imaging, resulting in satisfactory ultrasound images. Exclusion criteria comprised patients below 18 years of age, individuals with a known history of contrast agent allergy, kidney transplantation, polycystic kidneys, renal malignancies, renal artery stenosis, a life expectancy of less than 24 hours, hemodynamic instability (including persistent hypotension with a blood pressure below 90/60 mmHg), uncontrolled cardiac insufficiency, active bleeding (such as gastrointestinal and cerebral hemorrhage), or a bleeding tendency with a hemoglobin level below 60 g/L or platelet count below 50×10⁹/L. Patients with concurrent biopsy-proven severe glomerulopathy that contributed to AKI were also excluded from the study, as were patients with a clinical or pathological diagnosis of diabetic nephropathy. The control group consisted of healthy volunteers with normal kidney function.

The study received approval from the Ethics Committee on Research Ethics of Peking University First Hospital in 2021 (approval number:2021Y392). All human experimental methods were carried out following the principles outlined in the Declaration of Helsinki on Biomedical Research and informed consent was obtained from all participants. Figure 1 presents a flow diagram illustrating the study population, while Figure 2 depicts the study procedure.

The primary aim of this study was to observe the peak intensity (PI), rise time (RT), time to peak (TTP), and mean transit time (mTT) generated by CEUS for the cortex and medulla. Additionally, we evaluated the shear wave velocity of the renal cortex using point shear wave elastography (p-SWE), which reflects tissue rigidity. We compared the differences in these parameters between the AKI subgroup with renal outcomes and the control group. The secondary outcome focused on conducting a correlation analysis between ultrasonography-derived parameters and renal pathology.

CEUS in combination with conventional and elastography ultrasonography

Ultrasonography exams were conducted within 3 days of renal biopsy using a 3.5–5 MHz convex transducer on an Acuson S3000 machine. Patients were positioned laterally, and measurements of the right kidney's length, width, and thickness of the right kidney were obtained in the longitudinal and transverse planes. Color Doppler imaging assessed resistive index (RI) in the main and segmental renal arteries. For the abdominal mode, a nonpressurized hold was applied to the right kidney to minimize pressure interference during elasticity measurements. The ROI was strategically placed at the midpoint of the renal cortex to measure shear wave velocity, indirectly reflecting the rigidity of renal parenchyma. Cooling intervals were observed between measuring sessions, and a five-second cooling period preceded each subsequent measurement. This protocol was repeated ten times for each patient. Figure 3 portrays SWV measurements of the cortex in stage 1 (show in Fig. 3A) and stage 3 (show in Fig. 3B) patients.

For CEUS, grayscale ultrasound served as the base, and a maximum longitudinal plane was chosen to encompass the entire kidney before activating the CEUS mode. Prior to conducting the CEUS examination, patients were instructed to adopt shallow breathing patterns to minimize the impact of respiratory movements on image post-processing. The mechanical index was set at 0.10 to minimize microbubble damage. The contrast agent Sonovue® (Bracco, Italy) was selected and administered intravenously in a 1.2 mL bolus, immediately followed by a rapid injection of 5 mL of normal saline. The infusion allowed for sequential visualization of the contrast agent in the renal artery, cortex, and medulla, thus enabling continuous observation and recording of the intrarenal microcirculation process for a duration of three minutes. All images and video clips were digitally stored on a hard disk system and subsequently transferred to a computer for detailed quantitative analysis using Sonoliver software (TomTec Imaging Systems, Munich, Germany).

The post-processing of CEUS image analysis was performed using Sonoliver software. Prior to analysis, motion compensation was applied to all sequences to correct for minor breathing artifacts. The reference ROI (measuring16×16 mm²) was drawn on the perirenal fat. Three ROIs of the same size were drawn in the renal cortex and medulla at the upper, middle, and lower poles, excluding the interlobar and arcuate arteries. To reduce measurement heterogeneity, the results of the three ROIs in the renal cortex and medulla were averaged. Figure 4 provides an example of the time-intensity curve (TIC) for the cortex (show in Fig. 4A) and medulla (show in Fig. 4B).

Parameters derived from the perfusion model in Tomtec software were used, namely PI, RT, TTP and mTT. PI is defined as the maximum intensity in the ROI relative to the PI of the reference ROI. RT is independent on the time origin. TTP represents the time difference from zero to the peak intensity. mTT is the time required to reach half of the maximum signal intensity. Additionally, ratios of cortical to medullary parameters were calculated, including PI, RT, TTP, and mTT ratios. Each ROI was analyzed three times, and the mean value of the perfusion and time-related parameters was obtained to mitigate the impact of the respiratory-induced transitional distance and ensure the accuracy of the analyses. Figure 5 presents the TIC parameters.

Laboratory and Pathological examinations

For all patients with AKI, serum creatinine and eGFR were regularly recorded at the time of diagnosis and during follow-up. The serum creatinine-based eGFR at the third month of follow-up was used to evaluate renal restoration.

In our study, we utilized specific indices to evaluate kidney injuries based on the renal pathology results. These indices included glomerulosclerosis (GS), active tubulointerstitial (TI) scores, and chronic TI scores. The GS score was calculated by summing the number of glomeruli with glomerular sclerosis, segmental sclerosis, and ischemic sclerosis, divided by the total number of glomeruli. Active TI injuries were assessed by considering the presence or absence of tubulitis and interstitial edema (scored as 0 or 1, respectively), as well as the severity of interstitial inflammatory cell infiltration (semi-scored from 1 to 4 points). Renal interstitial inflammation is defined as inflammatory cell infiltration and edema in the interstitium. The active TI score represented the total score considering tubulitis, interstitial edema, and inflammation. Similarly, the chronic TI score encompassed semi-scored items such as tubular atrophy, interstitial fibrosis, and interstitial fibrosis associated with inflammatory cell infiltrates, with each item assigned 0 to 4 points depending on the severity of the lesion.

Statistical analysis

All statistical analyses will be performed using SPSS software V.24.0, with a P-value less than 0.05 considered statistically significant. The Kolmogorov-Smirnov test was used to assess the normal distribution of the data. For normally distributed measurement data, the statistical description will be presented as mean ± standard deviation, while non-normally distributed data are reported as the median. Analysis of variance or non-parametric tests were used to analyze the data among the three groups. Independent sample t-tests or Mann-Whitney U tests were used to compare the data between the two groups. Pearson or Spearman correlation analysis was used to evaluate correlations.

In conclusion, CEUS enables the detection of the renal perfusion redistribution in patients with AKI. A reduced cortex-to-medulla PI ratio discloses the presence of medullary congestion. The correlation of chronic TI score with cortex-to-medulla ratios of PI, RT and TTP, might indicate varied regulation capabilities of individuals to AKI. Further investigation is necessary to validate the usefulness of CEUS-derived PI ratio as a functional parameter for diagnosis and predicting renal outcome.

Author contributions

Research idea and study design: TS, XW; data acquisition: JL, TS, XW, LC; data analysis/interpretation: XW, TS, JL, LC; statistical analysis: XW, TS; supervision or mentorship: TS, LC. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Data availability

The datasets generated during the current study are available in the Chinese Medical Research Registration Information System repository (https://61.49.19.26/login) on December 31, 2021: MR-11–22-003,503. Besides, the datasets used during the current study available from the corresponding author on reasonable request.

Competing Interests

All other authors declare no competing interests.

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Table 1. Comparison on ultrasound parameters between AKI subgroups and control

Parameters		Control (n=12)	eGFR＞25 (n=7)	eGFR＜25 (n=9)	P
eGFR		114.10±10.78	44.65±18.60	9.71±6.29	＜0.01
CEUS:Cortex	PIc	834.16 (529.86, 2148.06)	1074.59（320.88，3253.73）	664.41（428.49，1482.85）	0.794
	RTc	13.69±5.56	12.17±2.70	12.63±3.91	＞0.05
	TTPc	14.68±6.13	13.12±2.60	13.44±4.25	＞0.05
	MTTc	123.25±59.87	90.74±44.82	91.71±34.02	＞0.05
CEUS:Medulla	PIm	666.05 (224.78, 1173.45)	1067.87（449.53，5055.50）	690.75（408.59，2830.11）	＞0.05
	RTm	18.45±8.88	16.58±3.98	17.29±4.40	＞0.05
	TTPm	20.08±10.03	18.18±4.17	19.67±6.52	＞0.05
	MTTm	159.58±93.82	92.40±38.67	90.95±34.71	＞0.05
Cortex-to-medulla ratio	PIratio	1.28 (0.96, 1.75)	0.80±0.24^A	1.03±0.44	0.023
	RTratio	0.77±0.14	0.76±0.20	0.74±0.18	＞0.05
	TTPratio	0.76±0.14	0.75±0.21	0.71±0.19	＞0.05
	MTTratio	0.87±0.40	0.94±0.20	1.02±0.18	＞0.05
Scr		71.85 (55.89, 76.75)	158.63±52.49^A	643.00±348.86^A	＜0.01
Doppler	RI of renal main artery	0.60±0.07	0.63±0.07	0.72±0.08^AB	0.001
	RI of renal segmental artery	0.57±0.07	0.62±0.06	0.67±0.06^A	0.003
Conventional ultrasonography	Length	10.43±0.81	11.33±1.44	11.45±1.96	＞0.05
	Width	5.00±0.97	3.95（3.70，4.90）	5.73±1.21	＞0.05
	Parenchymal thickness	1.85±0.39	1.45±0.16^A	1.92±0.37^B	0.022
Elastography(p-SWE)	SWV	2.24±0.78	1.72±0.72	1.57±0.59^A	0.044

Note: Data are mean ± standard deviation or median (25th-75th percentile)

A：Compared to the control group, the difference is statistically significant with a p-value of less than 0.05；B：Compared to the eGFR＞25 group, the difference is statistically significant with a p-value of less than 0.05

No competing interests reported.

supplementaryTables.docx

The Characteristics of Renal Microperfusion in Acute Kidney Injury: Initial Experience with Quantitative Contrast-Enhanced Ultrasound

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Abstract

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Introduction

Results

Discussion

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Conclusions

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Supplementary Files

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