Detection and size measurements of kidney stones on virtual non-contrast reconstructions derived from dual-layer computed tomography in an ex vivo phantom setup

Objectives To systematically investigate the usability of virtual non-contrast reconstructions (VNC) derived from dual-layer CT (DLCT) for detection and size measurements of kidney stones with regards to different degrees of surrounding iodine-induced attenuation and radiation dose. Methods Ninety-two kidney stones of varying size (3–14 mm) and composition were placed in a phantom filled with different contrast media/water mixtures exhibiting specific iodine-induced attenuation (0–1500 HU). DLCT-scans were acquired using CTDIvol of 2 mGy and 10 mGy. Conventional images (CI) and VNC0H-1500HU were reconstructed. Reference stone size was determined using a digital caliper (Man-M). Visibility and stone size were assessed. Statistical analysis was performed using the McNemar test, Wilcoxon test, and the coefficient of determination. Results All stones were visible on CI0HU and VNC200HU. Starting at VNC400 HU, the detection rate decreased with increasing HU and was significantly lower as compared to CI0HU on VNC≥ 600HU (100.0 vs. 94.0%, p < 0.05). The overall detection rate was higher using 10 mGy as compared to 2 mGy protocol (87.9 vs. 81.8%; p < 0.001). Stone size was significantly overestimated on all VNC compared to Man-M (7.0 ± 3.5 vs. 6.6 ± 2.8 mm, p < 0.001). Again, the 10 mGy protocol tended to show a better correlation with Man-M as compared to 2 mGy protocol (R2 = 0.39–0.68 vs. R2 = 0.31–0.57). Conclusions Detection and size measurements of kidney stones surrounded by contrast media on VNC are feasible. The detection rate of kidney stones decreases with increasing iodine-induced attenuation and with decreasing radiation dose as well as stone size, while remaining comparable to CI0HU on VNC ≤ 400 HU. Key Points • The detection rate of kidney stones on VNC depends on the surrounding iodine-induced attenuation, the used radiation dose, and the stone size. • The detection rate of kidney stones on VNC decreases with greater iodine-induced attenuation and with lower radiation dose, particularly in small stones. • The visibility of kidney stones on VNC ≤ 400 HU remains comparable to true-non-contrast scans even when using a low-dose technique. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-022-09261-w.


Introduction
Hematuria and urolithiasis rank among the most common urologic diagnoses, with urolithiasis being one of the leading causes of hematuria [1,2]. While the prevalence of hematuria has been reported between 2.4 and 31.1%, the lifetime prevalence of urolithiasis is approximately 15% in developed countries [2,3]. In patients with suspected urolithiasis, noncontrast computed tomography (CT) and in patients with hematuria and a high risk for genitourinary malignancy, multiphasic CT is recommended by international guidelines authored by the European Association of Urology (EAU) and the American Urological Association, respectively [3,4]. Due to the rising prevalence of urolithiasis and a high rate of recurrence of up to 50%, limiting radiation exposure in these and other urologic patients is a major concern [4,5].
In recent decades, technical advances allowed for extensive investigations regarding the reduction of radiation dose in computed tomography. This leads to the implementation of low-dose scanning protocols for patients with suspected urolithiasis in the international guideline by the EAU [4,[6][7][8]. On the contrary, the radiation dose of multiphasic CT in patients with hematuria including a non-contrast, parenchymal and excretory phase still exhibits a high radiation dose. Here, virtual non-contrast reconstructions (VNC) of excretory phase derived from dual-energy CT systems showed promising results in urinary stone detection to replace true non-contrast scans [9,10]. More recently, split-bolus protocols have been described to further reduce radiation dose by combining the parenchymal and excretory phase of the multiphasic hematuria CT protocol. Hence, when applied to dual-energy CT (DECT) systems, the non-contrast, parenchymal and excretory phase may be obtained within a single scan yielding a radiation dose reduction of up 40 to 60% [11,12]. So far, previous studies investigated the detection of kidney stones on VNC of the excretory phase using the different available emission-based DECT systems. To the best of our knowledge, there is no study available investigating the effect of different parameters using VNC of the dual-layer DECT system (DLCT). In particular, information on the performance of DLCT regarding detectability and size measurements of kidney stones is unavailable; however, both frequently determine treatment strategies in patients with kidney stones [1,4,12,13].
Hence, the aim of this study was to investigate the effects of different degrees of surrounding iodine-induced attenuation and radiation dose on the detection rate and size measurements of kidney stones on VNC obtained from DLCT.

Material and methods
This retrospective study was classified as non-human research by the local institutional review board. Kidney stones are routinely collected from surgical treatment procedures and chemical stone composition is routinely analyzed at the local laboratory using infrared spectroscopy. The reference standard of the stone size for subsequent analyses was obtained using a mean out of two measurements of the long-axis diameter with a vernier caliper (Man-M). For this study, 96 stones with a minimum long-axis diameter of 3 mm were initially included, of which 4 stones fractured during handling and were therefore excluded from the final analysis. Hence, this study comprised 92 kidney stones representing the clinically encountered variability: brushite (n = 11), cystine (n = 10), dahllite (n = 11), struvite (n = 7), uric acid (n = 12), weddellite (n = 12), whewellite (n = 20), and xanthine stones (n = 9) ( Table 1).

Phantom design
For all examinations, the stones were placed on a layer of gelatine (Oetker) exhibiting water-equivalent HU within polystyrene 24-well plates (surface area 1.9 cm 2 ; Corning Inc), to ensure a sufficient distance to the base plate for accurate stone size assessment using semi-automatic segmentation. The well plates were then filled with increasing amounts of iohexol (Accupaque, GE Healthcare) in water yielding an iodineinduced attenuation of 0 HU, 200 HU, 400 HU, 600 HU, 800 HU, 1000 HU, and 1500 HU. Corresponding contrast media/ water ratios were calculated based on a linear formula derived from a prior performed dilution series. The well plates were placed on a platform in a plastic box filled with water (width x height: 280 x 200 mm), which was positioned along the z-axis on the CT table and centrally within the gantry (Fig. 1). The procedure was repeated for each scan with a different iodineinduced attenuation. In between each scan with increasing iodine-induced attenuation, kidney stones were washed in saline to minimize possible absorption and accumulation of contrast media on the surface of the stones. Prior to each scan, a test scan of the different contrast media/water mixtures was acquired to ensure accurate iodine-induced attenuation and mixtures were adjusted if necessary. Attenuation values were quantified by placing two circular regions of interest within the mixtures. Here, attenuation values ± 10 HU of the desired iodine-induced attenuation were considered sufficient (ESM 1).

Scanning parameters and image acquisition
All scans were performed on a clinical DLCT scanner (IQon, Philips Healthcare). Tube current time products were set at 22 and 111 mAs resulting in a volumetric computed tomography dose index (CTDI vol ) of 2 and 10 mGy, respectively. Other relevant scan parameters were as follows: tube voltage = 120 kVp, collimation = 64 x 0.625 mm, matrix = 512 x 512, rotation time 0.5 s, and pitch 0.578. Conventional images (CI) were reconstructed for scans with water (CI 0HU ) using a hybrid-iterative reconstruction algorithm (iDose 4 , kernel B, level 3, Philips Healthcare). VNC were reconstructed for scans with iodine-induced attenuation of 200-1500 HU (VNC 200-1500HU ) using a dedicated spectral reconstruction algorithm (Spectral, kernel B, level 3; Philips Healthcare). Images were reconstructed in axial reorientation using a slice thickness and section increment of 0.67 mm, respectively.

Image analysis
Data sets were saved in DICOM format. Image analysis was performed on CI 0HU and VNC 200-1500HU using a soft-tissue window setting (width = 360 HU, level = 60 HU). First, two readers with two and five years of experience in abdominal imaging assessed the visibility of kidney stones in a consensus reading using a clinical DICOM viewer (Impax EE R20, Dedalus Group). Second, all visible stones were semiautomatically segmented by the first reader using an attenuation threshold-based algorithm implemented in an opensource DICOM image viewer (Horos v3.0, licensed under GNU Lesser General Public License). In a chosen subset of 24 stones comprising three of each available stone composition, the second reader repeated the segmentation to assess interrater reliability. The lower cut-off value was defined as 50 HU and was adjusted if needed to prevent the inclusion of any surrounding tissue, respectively. The upper cut-off value was set to maximum (i.e., 3072 HU). To assess the maximum diameter of each 3-dimensional volume of interest of every visible stone, an in-house developed script was employed (MATLAB 2019a, The MathWorks, Inc.) [14]. The two readers were free to adjust window settings when determining visibility and segmentation correctness To compare the detection rate between CI 0HU and VNC 200-1500HU as well as CTDI vol of 2 and 10 mGy, the McNemar test was applied. To compare the detection rate between the different stone compositions and stone sizes, fisher's exact test was applied. To compare detection rates between different stone compositions, a subset of 32 stones with comparable manually measured stone sizes were chosen (Table 1).

Statistical analysis
Stone size measurements were compared using Wilcoxon signed rank test. The correlation between CT measurements of the longest diameters and Man-M was determined using the coefficient of determination. Interrater reliability was determined by means of intra-class correlation estimates (intraclass correlation coefficient (ICC)) based on a single rater, consistency, 2-way mixed-effects model for the CT-based size

Kidney stone detection
All stones were detected on CI 0HU and VNC 200HU . Starting at VNC 400 HU , the detection rate decreased on VNC with increasing iodine-induced attenuation and was significantly lower on VNC ≥ 600HU as compared to CI 0HU and VNC ≤ 400 HU (p < 0.001). Simultaneously, the detection rate on VNC 600HU was significantly higher as compared to VNC ≥ 800HU as well as significantly higher on VNC 800HU and VNC 1000HU as compared to VNC 1500HU (p < 0.001, respectively) (

Influence of radiation dose on detection rate
The overall detection rate of kidney stones was significantly higher in the high-dose protocol as compared to the low-dose protocol (87.9 vs. 81.8%; p < 0.001). Regarding similar iodine-induced attenuation, the detection rate was higher in scans using the high-dose protocol as compared to the lowdose protocol on VNC ≥400 HU reaching a statistical significance at VNC ≥ 800HU (VNC 800HU : 90.2% vs. 75.0%, p < 0.001) ( Table 2 and Fig. 2B). The detection rate remained comparable to CI 0HU on VNC ≤ 400 HU when using the lowdose (2 mGy) and on VNC ≤ 600HU when using the high-dose protocol (10 mGy) (p < 0.05).

Kidney stone size measurements
Regarding CT-based size measurements, mean ICC was 0.923 (0.907-0.936), indicating excellent interrater reliability. Across all stones, the manually measured size was 6.7 ± 2.8 mm ranging from 3.0 to 14.0 mm, while CT-based measurements were higher when averaging all reconstructions (7.1 ± 3.5 mm; p < 0.001).

Discussion
This study investigated the effects of different degrees of surrounding iodine-induced attenuation and radiation dose on the detection rate and size measurements of kidney stones on VNC obtained from DLCT. We found that the overall detection rate continuously decreased with increasing surrounding iodine-induced attenuation, while remaining comparable to true-non-contrast scans on VNC ≤ 400 HU even when using a low-dose technique. The detection rate of kidney stones was higher in the high-dose protocol as compared to the low-dose protocol and was comparable between both protocols on VNC ≤ 600HU . Kidney stone size influenced the detection rate and was generally overestimated. Stones > 5 mm were better detected than stones ≤ 5 mm, while the detection rate remained comparable on VNC ≤ 800HU . The reported data demonstrate the beneficial value of VNC derived from dual-energy CT in the imaging of hematuria and urolithiasis. VNC has the potential to replace the true noncontrast scan in multiphasic CT protocols resulting in a reduction of radiation dose, while maintaining a high detection rate of kidney stones when taking the observed limitations into account. To the best of our knowledge, our study represents the first study investigating the detection of kidney stones on VNC derived from DLCT, while most published in vivo studies used rapid-switching rather than dual-source DECT [18]. A direct translation of the presented results to other DECT systems is limited due to different technical aspects, such as a reported variation in iodine quantification accuracy between the different DECT systems-which, in turn, closely relates with VNC accuracy [19,20]. Yet it has been shown that iodine can be accurately quantified with all state-of-the-art DECT systems including DLCT [19][20][21]. Nonetheless, future studies are encouraged to perform a true head-to-head comparison.
Earlier studies already reported an insufficient subtraction of iodine and a decrease in the detection rate of kidney stones at an attenuation of 600-730 HU, which is in line with the results of this study [1,22]. However, the luminal attenuation in the renal pelvis during the excretory phase may exceed these values possibly hampering kidney stone detection on VNC [10]. Hence, different split-bolus protocols have been investigated to limit the luminal attenuation in the renal pelvis, e.g., Chen et al were able to limit the attenuation of the renal pelvis to 457.2 ± 168.8 HU and reported a detection rate of 87.5 % on VNC when using a bolus of 200 mL saline, followed by 50 mL contrast media (300 mg iodine/mL) 6 minutes prior to the second bolus of 70 mL contrast media, followed by 24 mL saline and scanning delay of 60 seconds [23]. More recently, McCoombe et al published a systematic review and metaanalysis of in-vivo studies on the detection rate of kidney stones on VNC of excretory phase obtained from split-bolus DECT. The authors reported the highest pooled sensitivity of 92.2 % on VNC compared to true non-contrast scans in a subgroup analysis of studies that used oral hydration and < 2 mm slice thickness [18]. Future studies should take vital parameters such as heart rate and blood pressure as well as the glomerular filtration rate into account when investigating new optimization possibilities of split-bolus protocols as these might affect the excretion of contrast agent.
Other studies demonstrated that kidney stone size influences the detection rate on VNC [1,9,10,24]. In line with these studies, we found a difference in size between visible and invisible stones as well as a positive correlation between stone size and detectability. Considering a general cut-off for insignificant stones of ≤ 5 mm described by current guidelines [4,17], our results showed a significantly better detectability for stones > 5 mm, which remained as high as 85 % on VNC 1000HU . Yet, it has to be mentioned that stones smaller than 5 mm might also cause symptoms and might not pass spontaneously, although up to 95 % of kidney stones smaller than 4 mm pass spontaneously [4,17,25]. More particular detection of small stones may be diagnostic in the scenario of unclear hematuria (irrespective of the impact on treatment). Furthermore, previous studies reported an underestimation of kidney stone size on VNC compared to true non-contrast images due to an over-subtraction of small stones or of the peripheral stone along with the iodine signal [1,9,10]. Contrary, CT-based stone size in this study was generally overestimated compared to Man-M, which is e.g. discrepant to an earlier ex-vivo study of Lazar et al using a DSCT system, performing 2D-based size measurements on axial reconstructions and including smaller stones with a diameter of 2.4 ± 1.1 mm in which the over-subtraction may have a higher influence on size measurements [1]. A possible explanation for this behaviour might lie in the different scanner techniques and hence post-processing capabilities used between the studies.  Additionally, it has been shown that measurements taking the three-dimensional irregular structure of kidney stones by means of volumetric CT-based measurements or multiplanar reconstructions into account might be a better predictor of treatment outcome and showed closer agreement with true stone size [26][27][28].
Besides, the detectability and size assessment of small kidney stones using low-dose protocols in the non-contrast imaging of urolithiasis as recommended by current guidelines has been extensively investigated in previous studies. These studies demonstrated high diagnostic accuracy and accurate size assessment of small stones with a diameter of less than 3 mm as compared to high-dose protocols [7,14,29,30]. Pertaining to the detection of kidney stones surrounded by iodine-induced attenuation on VNC, our study showed comparable detectability between the low-and high-dose protocol on VNC ≤ 600HU as well as comparable size measurements. Hence, a further reduction of radiation dose in clinical studies of the imaging of hematuria seams conceivable, since previous in-vivo and ex vivo studies only investigated radiation doses as low as 6 and 10 mGy [1,10].
In addition, non-contrast dual-energy CT showed better differentiation of stone composition compared to polyenergetic CT, even when using a low-dose technique [31,32]. So far, only Lazar et al analysed the effect of stone composition on the detection rate of kidney stones on VNC and reported the best detectability for cystine stones, followed by struvite, brushite, and whewellite stones [1]. On the contrary, we found higher detection rates for calcium (whewellite, weddellite, dahllite, brushite) and xanthine stones (> 80%) as compared to uric acid, cystine and struvite stones (< 80%) without reaching a statistical significance. Besides, DECT type-dependent differences, these discrepancies may also result from the inclusion of larger stones in our analysis.
In light of the presented data and discussed literature, VNC may reduce the radiation dose in the imaging of hematuria by replacing TNC if the surrounding attenuation in the renal pelvis is ≤ 400 HU irrespective of radiation dose. A possible clinical approach in unknown hematuria consists of a single acquisition split-bolus protocol including the interpretation of VNC images and, in case of no identifiable cause of hematuria and the attenuation in the renal pelvis exceeding 400 HU, an additional low-dose TNC acquisition can be considered for increased detection of small stones, which might have clinical relevance in this specific contrast as a cause of hematuria.
Apart from the limited number of stones included per stone composition, there are several limitations to this study. First, this is an ex vivo study. However, the highly standardized phantom setup allowed us to perform a thorough investigation of the different parameters, which would not be possible in an in-vivo setting. Second, we adopted the radiation dose protocols from previous studies and from our institutional settings [8,26,31]. However, the image quality obtained in our ex vivo setup may not translate into in-vivo applications. While the used phantom diameter of 280 mm is close to the diameter of the general body phantom (320 mm) used for CT dosimetry, the homogeneous attenuation of water does not represent in vivo conditions and possibly results in an underestimation of radiation dose as compared to the in-vivo setting [33]. Furthermore, it is known that the detection of kidney stones on TNC is hampered in patients with high body mass indices due to a decrease in image quality, which is yet to be shown for VNC [34]. Last, the ex vivo conditions resulted in a bias as to in which position a stone would be expected and will therefore likely overestimate detection rates as compared to a true patient study. Studies addressing this in-vivo detectability of renal stones are encouraged in order to adapt our findings into clinical workflow.
To conclude, detection and size measurements of kidney stones surrounded by contrast media on VNC are feasible, which may reduce radiation dose by replacing true noncontrast scans. The detection rate of kidney stones depends on the surrounding iodine-induced attenuation, the used radiation dose, and kidney stone size. In particular, stones are expected to be detectable in VNC if surrounding attenuation is ≤ 400 HU irrespective of radiation dose.

Declarations
Guarantor The scientific guarantor of this study is PD Dr. med. Nils Große Hokamp. Statistics and biometry RPR, SL, and NGH have significant statistical expertise.

Conflict of interest
Informed consent Written informed consent was not required for this study because this is a non-human research.
Ethical approval Institutional Review Board approval was not required because this is a non-human research.

Methodology
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