A method for measuring glomerular filtration rate in a subject ex vivo.

Abstract

The present invention relates to a method for ex vivo measuring the glomerular filtration rate (GFR) of a subject who has been administered a contrast agent and has undergone computed tomography (CT) or magnetic resonance imaging (MRI) including an excretion phase, a simple phase, an arterial phase, and a renal parenchymal phase or a venous portal phase, the method comprising the steps of calculating the clearance of the contrast agent from the CT or MRI data using manual, automatic, or semi-automatic segmentation software, and thereby obtaining the measured GFR.

Description

[Technical Field]

[0001] The present invention relates to a method for measuring the glomerular filtration rate (GFR) in a subject ex vivo.

[0002] Therefore, the present invention is effective in the medical field, particularly in the fields of diagnosis and patient monitoring.

[0003] In the following explanation, references in square brackets ([]) refer to the list of references at the end of this document. [Background technology]

[0004] Glomerular filtration rate (GFR) is a primary variable used to assess renal function. It is particularly used for adjusting the dosage of drugs excreted by the kidney or for making various clinical decisions. In clinical practice, GFR is estimated from formulas based on serum or plasma concentrations of endogenous markers such as creatinine or cystatin C. One major limitation of estimated GFR (eGFR) is its inaccuracy, and creatinine and Neither eGFR nor cystatin C-based calculations have an accuracy of less than 30% across all age groups, well over 90%. This means that in at least one in ten patients, eGFR overestimates measured GFR (mGFR) by more than 30% or underestimates it by less than -30%. Risk factors for the inaccuracy of creatinine-based eGFR are conditions that affect non-GFR determinants of serum creatinine concentration, namely atypical muscle mass, an extremely high-protein diet or conversely a vegetarian diet, or the use of drugs that block tubular creatinine secretion. When knowing the true GFR value is required for clinical decision-making, GFR can be measured by assessing the clearance of exogenous tracers (Ebert N et al.[1]). These procedures are cumbersome, time-consuming (at least 4-5 hours, and sometimes up to 24 hours), and consequently costly.

[0005] The need to develop a simple, rapid, and reproducible method for measuring GFR remains unmet to this day. Although older and more recent studies have evaluated the practicality of measuring GFR from CT scans using various particularly specialized acquisition protocols (Yuan X et al. ([2]), You S et al. ([3]), Hackstein N et al. ([4]), Hackstein N et al. ([5]), Jeong S, Park SB et al. ([6])), they are not necessarily used in routine clinical practice, which may explain why they have not become widespread. Historically, two-compartment mathematical models were the first to be used. Most of them were based on the Patlak plot model, originally developed to measure constant movement across the blood-brain barrier (Patlak CS et al. ([7])). In this model, which considers only vascular and tubular compartments, it was assumed that tracers irreversibly diffuse from the vascular compartment to the tubular compartment with a movement coefficient corresponding to GFR. The interstitial region was not considered because it is quantitatively variable from subject to subject. The outflow of tracers into the excretory tract was also not considered. This model, whether original or modified, did not work very well in measuring GFR (Hackstein N et al. ([4]), Hackstein N et al. ([5])). More recently, two groups have proposed methods for measuring GFR (iobromide clearance) based on both CT scans and biological (hematocrit) (Yuan X et al. ([2]), You S et al. ([3])). UAN et al. used perfusion CT scans with multiphase dynamic acquisition, an acquisition method not used in clinical routines, in 42 patients. 99mThe protocol showed very good agreement with Tc-DTPA plasma clearance (Yuan X et al. ([2])). You et al.'s protocol also had very strictly defined acquisition parameters, along with a simple phase, a renal parenchymal phase (precisely 100 seconds after bolus infusion), and an excretion phase (precisely 600 seconds) (You S et al. ([3])). This protocol appeared to have a less favorable agreement than GFR measured by the Gates method (You S et al. ([3])), and the Gates method itself is not a standard method for GFR measurement and is potentially about as accurate as creatinine-based eGFR (Yuan X et al. ([2]), Aydin F et al. ([8]), Itoh K. ([9]), Kumar M et al. (

[10] )). These two methods for measuring GFR share the drawback that they cannot be retrospectively used from CT urography performed in routine practice. Furthermore, in both cases, the hematocrit value is included in the GFR calculation, which also makes it somewhat impractical.

[0006] Therefore, there is a need for alternative methods for measuring GFR. The present invention satisfies the above and other needs. [Overview of the project]

[0007] Surprisingly, the applicant has used computed tomography (CT) or magnetic resonance imaging (MRI) on the subject. We found that glomerular filtration rate (GFR) can be measured by evaluating contrast agent clearance from opportunistic imaging.

[0008] Surprisingly, segmentation of various regions of interest at different relevant time points in opportunistic imaging allows for the calculation of contrast agent clearance, i.e., glomerular filtration rate in the subject.

[0009] The inventors have shown that GFR measured by opportunistic imaging is unbiased and has excellent agreement with GFR measured by laboratory iohexole clearance (absolute standard).

[0010] After thorough research, the inventors succeeded in developing a highly reliable method for measuring GFR despite wide variability in imaging procedures, and demonstrated its usefulness particularly in opportunistic value-added imaging approaches.

[0011] Therefore, in a first embodiment, the present invention relates to a method for measuring GFR in a subject ex vivo, comprising the following steps: 1) Step of administering contrast agent to the target, 2) The step of performing imaging on the subject, including computed tomography (CT) or magnetic resonance imaging (MRI), which includes the excretion phase, simple phase, arterial phase, and renal parenchymal phase or venous portal phase. 3) A method is provided which includes the step of calculating the clearance of contrast agent from the CT or MRI data obtained in step 2) using manual, automatic, or semi-automatic segmentation software, and thereby obtaining the measured GFR.

[0012] In other words, the present invention is a method for ex vivo measuring the GFR of a subject to which a contrast agent has been administered and a CT or MRI has been performed including a simple phase, an arterial phase, a renal parenchymal phase or a venous portal phase, and an excretion phase, wherein the GFR is calculated from the CT or MRI data using manual, automatic, or semi-automatic segmentation software, and measured accordingly. The present invention provides a method that includes the step of obtaining a GFR.

[0013] A contrast agent, also referred to herein without distinction as "contrast media," can be an ideal exogenous marker for measuring GFR, as it freely diffuses into extracellular volume, is not metabolized, does not bind to plasma proteins, is freely filtered and therefore eliminated only by the kidney, and is not secreted or reabsorbed into the renal tubules. It can be any substance that enables an increase in the contrast of structures or fluids within the body in medical imaging. A contrast agent can be, for example, an iodinated or uniodized drug. A contrast agent can be, for example, an iodine or gadolinium-based contrast agent. Iodine-based contrast agents can be selected from, for example, iomeprole, iohexol, iopamidol, ioxiran, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iotalamate, and ioxagrate. Gadolinium-based contrast agents include, for example, gadopentetate dimeglumine (gadolinium diethylenetriamine pentaacetic acid, Gd-DTPA), gado Diamides (gadolinium diethylene triamine penta-acetic acid bis-methylamide, GD-DTPA-BMA), gadoteridol (gadolinium-1,4,7-tris(carboxylmethyl)-10-(2'hydroxypropyl)-1,4,7-10-tetraazacyclododecane (Gd-HPD03A)), gadoteric acid meglumine (gadolinium-tetraazacyclododecane tetraacetic acid (Gd-DOTA), Dotarem® or Clariscan), gadoteric acid, gadopentic acid, and their salts such as gadopentic acid dimeglumine, gadoxetic acid, and gadobutrol can be selected.

[0014] Advantageously, the contrast agent used may be iomeprol. Iomeprol is a low-viscosity, low-osmolality, nonionic, water-soluble, iodized contrast agent. Its molecular weight of 777.09 daltons is slightly smaller than that of iohexol (821.1 Da) or iotalamate (809.1 Da). Furthermore, iomeprol does not bind to plasma proteins to a measurable extent. These chemical properties make iomeprol a potentially ideal exogenous marker for measuring GFR, i.e., it diffuses freely into extracellular volume, is not metabolized, does not bind to plasma proteins, is freely filtered and therefore eliminated only by the kidney, and is not secreted or reabsorbed into the renal tubules. Pharmacokinetic studies revealed that after a bolus infusion of iomeprol, its plasma concentration decreased exponentially (the first slope corresponding to its diffusion in extracellular volume and its renal clearance, and the second slope corresponding to its renal clearance only). Extrarenal clearance was negligible, and a very good correlation was found between this clearance and inulin clearance.

[0015] The administration of the contrast agent to the subject may be carried out by any standard means, depending on the type of agent. This may be, for example, intravenous injection. Preferably, the contrast agent is administered to the subject before carrying out the method of the present invention; that is, the step of administering the contrast agent is not part of the method of the present invention.

[0016] The concentration of administered contrast agent in the blood, urine, and / or renal parenchyma can be determined by any method known in the art. This may be Hunsfield unit counting, or other methods such as iodine quantification with a spectral CT detector, photon counting CT, or MRI signal intensity. It should be noted that spectral imaging allows for the direct measurement of iodine basis weight without requiring spontaneous contrast acquisition. Therefore, in spectral imaging and photon counting CT imaging, the simple CT phase is not required to calculate GFR, as all measurements performed correspond to an iodine basis weight equal to zero in the simple phase. Thus, in spectral and photon counting CT, the simple CT phase is optional as it contributes nothing to the results. In other words, in spectral imaging, the excretion phase, kinetic Only the pulse phase and either the renal parenchymal phase or the venous portal phase may be performed.

[0017] Advantageously, the method of the present invention can be applied without considering the amount of contrast agent administered, even when the dose of the contrast agent is reduced, for example, to less than 1 ml / kg for iodized contrast agents.

[0018] The subjects may be healthy individuals or individuals with kidney disease, such as chronic kidney disease.

[0019] "Imaging", as used herein, refers to any medical imaging technique and process that creates data, particularly images, of the interior of the body. It can be computed tomography (CT) or magnetic resonance imaging (MRI). A CT scan can be, for example, multicolor computed tomography, spectral computed tomography, photon-counting computed tomography, sequential CT, spiral CT, electron beam tomography, dual-energy CT, CT perfusion imaging, or PET CT. An MRI scan can be contrast MRI, regardless of the magnetic field strength. Advantageously, it can be opportunistic imaging, such as the extraction of imaging biomarkers or features in an imaging examination performed for clinical objectives different from measuring GFR. Alternatively, it can be a CT or MRI examination performed solely for the purpose of measuring GFR. Preferably, the imaging is performed on the subject prior to the implementation of the method of the present invention, i.e., the imaging step is not part of the method of the present invention.

[0020] "Excretion phase", as used herein, refers to the time range after administration of a contrast agent in which optimal enhancement of the renal collecting system and bladder is present, at least about 7 minutes after injection of the contrast agent, for example about 10 minutes after injection of the contrast agent. Advantageously, this period allows the contrast agent to reach the bladder. In other words, it can be the period of urinary excretion of the contrast agent after glomerular filtration.

[0021] In one embodiment, in order to limit the X-ray dose in the case of CT imaging performed solely for the purpose of measuring GFR, the imaging can be limited to a single slice at the normal time of the arterial phase and the renal parenchymal phase or the venous portal phase. The arterial phase can also be limited to a single slice of the aorta of a healthy individual. In the case of a patient with renal disease, the arterial phase is preferably acquired over the entire height of the kidney in order to enable the study of the renal cortex and thus is not limited to a single slice. The excretion phase can include the renal parenchyma, the upper renal excretory system, and the bladder.

[0022] The plain phase may include the renal parenchyma and, optionally, may partially or entirely include the bladder, particularly when the iodine concentration cannot be directly measured in the post-IV acquisition. Alternatively, when the iodine concentration can be directly measured in the post-IV acquisition, particularly in spectral imaging, this acquisition is optional.

[0023] The arterial phase and / or the renal parenchyma (or portal venous) phase may include at least one aorta slice. If the bladder is not included in the plain phase, it may be partially or entirely included in the arterial phase or the renal parenchyma phase or the portal venous phase. In other words, if the renal parenchyma phase or the portal venous phase is not included in the plain phase, it may include at least one aorta single slice together with the bladder.

[0024] "Segmentation" as used herein refers to any process of dividing an image into regions having similar characteristics (such as tone levels, color, texture, luminance, and contrast, etc.) in order to subdivide the objects within the image. Automatic or semi-automatic segmentation software can be any state-of-the-art software such as ADW Server GE HealthCare, syngo.via Siemens, Carestream, Osirix, 3D Slicer, Total Segmentator, MONAI Auto3DSeg, etc., but this list is not limiting. For example, step 3) can be automatically performed using software developed from artificial intelligence, i.e., deep learning, or algorithms developed by other methods, particularly to determine both the urinary excretion of the contrast agent and the mid-term serum concentration.

[0025] Step 3), i.e., the step of calculating, can be performed entirely or partially by a computer. The computer can be any computer that calculates the clearance of the contrast agent using the method of the present invention. The computer may or may not be included in the automatic segmentation software.

[0026] Advantageously, contrast agent clearance can be calculated by dividing the urinary excretion rate of the contrast agent between the arterial and excretion phases by the calculated serum concentration of the contrast agent in the midterm. Advantageously, this calculation method may have at least one of the following advantages: - In particular, the possibility of using CT urography performed in a therapeutic context as part of an opportunistic imaging approach, compared to CT-based pharmacokinetic models such as Patlak's model ([7]) which requires dynamic acquisition not performed for therapeutic purposes, - Better accuracy than CT-based pharmacokinetic models, - Some conventional methods require hematocrit measurement, but do not require additional blood tests. - Compared to laboratory methods which take at least 4 hours and 30 minutes, and sometimes 24 hours, the test takes a very short time of about 7-10 minutes. - No need for blood or urine assays required for laboratory methods, or for specialized pharmacology or nuclear medicine laboratories. - Lower cost than laboratory methods. For example, urinary clearance of exogenous tracers requires a one-day hospital stay and costs over 1,000 euros in France, compared to approximately 150 euros for a CT scan. - It consumes less time for medical assistants than laboratory methods.

[0027] Accordingly, as described above, the present invention provides a method for ex vivo measuring the GFR of a subject to which a contrast agent has been administered and to which a CT or MRI including a simple phase, an arterial phase, a renal parenchymal phase or a venous portal phase and an excretion phase has been performed, preferably comprising the steps of calculating contrast agent clearance from CT or MRI data using manual, automatic, or semi-automatic segmentation software, wherein contrast agent clearance can be calculated by dividing the urinary excretion rate of the contrast agent between the arterial phase and the excretion phase by the calculated serum concentration of the contrast agent in the medium term, and obtaining the GFR measured thereby.

[0028] For example, the urinary excretion rate of contrast agent between the arterial phase and the excretion phase may be the sum of urinary excretion of contrast agent into the bladder (Uexcr-bladder), urinary excretion of contrast agent into the upper excretory tract (Uexcr-tract), and urinary excretion of contrast agent into the renal tubules (Uexcr-tubules). The intermediate serum contrast agent concentration can be estimated from linear regression or polynomial regression after converting each intermediate serum concentration equivalent to a natural logarithm.

[0029] In one embodiment, urinary excretion of contrast agent into the renal tubules (Uexcr-tubule) is calculated by multiplying the volume of both kidneys by the difference between the mean renal decay in the excretion phase (HU-kidney-excr) and the mean renal decay in the simple phase (HU-kidney-simple), and then dividing by the period. Advantageously, this embodiment is suitable for subjects with a normal GFR, i.e., healthy subjects, or at least 60 ml / min / 1.73 m³. 2 This can be performed on subjects with an estimated GFR based on creatinine or cystatin C equal to [a certain value].

[0030] In another embodiment, urinary excretion of contrast agent into the renal tubules (Uexcr-tubules) is the sum of urinary excretion of contrast agent into the renal medulla and urinary excretion of contrast agent into the renal cortex. Advantageously, this embodiment is suitable for subjects with low GFR, i.e., diseased subjects, or those with a GFR of 60 ml / min / 1.7 3m 2 This method may be performed on subjects with an estimated GFR based on lower creatinine or cystatin C, or on healthy subjects, because this calculation method yields results very similar to the first method described above for those subjects. For example, in the case of CT: - The urinary excretion of contrast agent into the renal medulla can be calculated by multiplying the volume of the renal medulla by the difference between the mean renal CT attenuation in the excretion phase (HU-kidney-excr) (which is the same as that of the medulla, and the renal parenchyma is homogeneous in this CT phase) and the mean renal attenuation in the simple phase (HU-kidney-simple) (the renal parenchyma is also homogeneous in this CT phase), and then dividing by the period. - The urinary excretion of contrast agent into the renal cortex may be calculated by multiplying the volume of the renal cortex by the mean renal CT attenuation in the excretion phase (HU-kidney-excr) (which is the same as that of the cortex, as the renal parenchyma is homogeneous in this CT phase), subtracting the renal CT attenuation in the simple phase from the mean renal CT attenuation in the excretion phase (HU-kidney-excr) (which is the same as that of the cortex, as the renal parenchyma is homogeneous in this CT phase), further subtracting the cortical CT attenuation from the vascular compartment in the excretion phase (corresponding to the presence of contrast agent in the cortical vascular compartment in this excretion phase), and then dividing by the time between the arterial phase and the excretion phase. The cortical CT attenuation due to the vascular compartment in the excretion phase can be calculated as follows: First, determine the ratio between cortical enhancement and aortic enhancement in the arterial phase, and then multiply this ratio by the uptake of contrast agent in the aorta in the excretion phase. The ratio between cortical enhancement and aortic enhancement in the arterial phase is obtained by subtracting the renal CT attenuation in the simple phase from the renal cortical CT attenuation in the arterial phase, and then dividing that by subtracting the aortic CT attenuation in the simple phase from the aortic CT attenuation in the arterial phase. The uptake of contrast agent in the aorta during the excretion phase is the difference between the CT attenuation of the aorta in the excretion phase and the CT attenuation of the aorta in the plain phase.

[0031] To measure the urinary excretion of contrast agent from the bladder, the measurement of bladder volume and its mean decay during the excretion phase may include either the entire bladder volume or only a portion of the bladder in the declivery zone containing the contrast agent.

[0032] Advantageously, specific areas of a CT scan or MRI scan can be segmented at different time points to determine the urinary excretion rate of the contrast agent.

[0033] Advantageously, aortic volume or a single slice can be used to measure aortic CT density or MRI signal.

[0034] The present invention is further illustrated by the following embodiments with respect to the attached drawings, which should not be construed as limiting. [Brief explanation of the drawing]

[0035] [Figure 1] This flowchart shows the study population (living kidney donors, i.e., healthy individuals). [Figure 2-1] This shows a concurring analysis between CT-mGFR and mGFR, as well as between eGFR and mGFR. CT-mGFR is determined in healthy individuals by calculating Uexcr-tubules without considering contrast products present in the cortical vascular compartment. Bland-Altman plots comparing CT-mGFR and mGFR(A), as well as CKD-EPI2021 and mGFR(B). The X-axis is the mean of the results obtained from the two GFR assessment methods. The Y-axis is the relative difference between the two GFR assessment methods. The solid line is the bias (mean relative difference), and the dashed lines are the lower and upper limits of the concurring interval (-1.96SD and +1.96SD). Relationships assessed by Passing Bablok regression between CT-mGFR and mGFR(C), and between CKD-EPI2021 and mGFR(D). The equations of the regression lines are shown in the graph in the figure. The dashed line is the identity line, and the thick line is the regression line. [Figure 2-2] This shows a concurring analysis between CT-mGFR and mGFR, as well as between eGFR and mGFR. CT-mGFR is determined in healthy individuals by calculating Uexcr-tubules without considering contrast products present in the cortical vascular compartment. Bland-Altman plots comparing CT-mGFR and mGFR(A), as well as CKD-EPI2021 and mGFR(B). The X-axis is the mean of the results obtained from the two GFR assessment methods. The Y-axis is the relative difference between the two GFR assessment methods. The solid line is the bias (mean relative difference), and the dashed lines are the lower and upper limits of the concurring interval (-1.96SD and +1.96SD). Relationships assessed by Passing Bablok regression between CT-mGFR and mGFR(C), and between CKD-EPI2021 and mGFR(D). The equations of the regression lines are shown in the graph in the figure. The dashed line is the identity line, and the thick line is the regression line. [Figure 3]This graph represents the inter-observer agreement with the Bland-Altman plot for CT-mGFR determined in healthy individuals by calculating Uexcr-tubules without considering contrast products present in cortical vascular compartments. The X-axis is the mean of results obtained from two consecutive GFR measurements. The Y-axis is the relative difference between the two GFR measurements. The solid line represents the bias (mean relative difference), and the dashed lines represent the lower and upper limits of the agreement interval (-1.96SD and +1.96SD). [Figure 4] This flowchart shows the study inclusion criteria for the chronic kidney disease population. [Figure 5]The parameters are derived from CT urography used to calculate contrast agent in the renal tubules, either by considering the renal parenchyma as a single entity or by calculating the contrast agent in the cortical tubules and the contrast agent in the medullary tubules separately. CT attenuation and / or volume measurements of the renal parenchyma and / or aorta necessary for calculating the urinary excretion of contrast agent in the renal tubules are provided in panels A, B, and C, which represent CT slices in the simple phase (A), arterial phase (B), and excretion phase (C). In panel D, the urinary excretion of contrast agent into the renal tubules (light gray area) is calculated by multiplying the volume of both kidneys by the mean attenuation of the kidney in the excretion phase minus the mean attenuation of the kidney in the simple phase, and then dividing by the period: 257.5 × (81.1 - 35.9) / 9.57 = 1216 HU × mL / min. In panel E, urinary excretion of contrast agent into the renal tubules was the sum of urinary excretion of contrast agent into the renal medulla (light gray area) and urinary excretion of contrast agent into the renal cortex (dark gray area). Urinary excretion of contrast agent into the renal cortex was calculated by multiplying the volume of the renal cortex by the mean CT attenuation of the kidney in the excretion phase minus the CT attenuation of the kidney in the simple phase, and further subtracting the cortical CT attenuation from the vascular compartment in the excretion phase (i.e., the ratio of cortical enhancement to aortic enhancement in the arterial phase, and then this ratio multiplied by the uptake of contrast agent in the aorta in the excretion phase), and then dividing by the time between the arterial phase and the excretion phase: 148.4 × (81.1 - 35.9 - (489.6 - 35. 9) / (943.9-40.3)×(76.6-40.3) / 9.57=418 HU×mL / min. The urinary excretion of contrast agent into the renal medulla was calculated by multiplying the volume of the renal medulla by the difference between the mean CT attenuation of the kidney in the simple phase and the mean CT attenuation of the kidney in the excretion phase, and then dividing by the period: (257.5-148.4)×(81.1-35.9) / 9.57=515 HU×mL / min. Therefore, the urinary excretion of contrast agent into the renal tubules was 418+515=933 HU×mL / min. [Figure 6]Bland-Altman plots showing the agreement between CT-measured GFR and mGFR. The x-axis represents the mean of GFR measurements obtained by the two assessment methods. The y-axis represents the relative difference between GFR measurements from the two assessment methods. The solid line is the bias (mean relative difference), and the dashed lines are the lower and upper limits of the agreement interval (-1.96SD and +1.96SD). Black dots represent 28 individuals, including patients with chronic kidney disease (CKD). White dots represent 75 previously reported healthy individuals. In Panel A, CT-mGFR was calculated assuming that the contrast agent in the renal parenchyma during the elimination phase was located only in the tubular compartment. In Panel B, the portion of renal cortical enhancement during the elimination phase due to the cortical vascular compartment was subtracted from the CT-mGFR calculation. [Figure 7] Bland-Altman plots showing inter-observer agreement between CT-mGFR determined by a senior nephrologist with 8 years of experience in GFR measurement and CT-mGFR determined by a senior radiologist with 5 years of experience in abdominal radiology in CKD patients. Each observer was not informed of the results obtained by the other observer, nor the results of GFR measurement by iohexol clearance. In Panel A, CT-measured GFR was calculated as described above, assuming that the contrast agent in the renal parenchyma during the excretion phase is located only in the tubular compartment. In Panel B, the portion of renal cortical enhancement during the excretion phase due to the cortical vascular compartment was subtracted from the CT-measured GFR calculation. [Examples]

[0036] Example 1: Iomeprole clearance evaluated by CT urography to measure GFR in living kidney donor candidates. method: Research design: This is a cross-sectional study using data from kidney donor candidates screened in hospitals from July 2016 to October 2022, using both GFR measurement by iohexol clearance and renal morphological evaluation by CT urography.

[0037] The Institutional Review Board of the inventors' institution approved this study:CSE-21-23_PEGMAS, and the patient gave informed consent.

[0038] Study population: All living kidney donor candidates surveyed in the nephrology department between July 2016 and October 2022 were eligible for inclusion. GFR was measured from iohexol clearance in all of these individuals according to the KDIGO guidelines (Lentine KL et al. (

[11] )). The only inclusion criterion was that CT urography for the same period (regardless of whether the CT scan was performed in-hospital or out-of-hospital) was available in the hospital's image storage and communication system. CT urography had to include four polychromatic acquisition phases (simple phase, arterial phase, renal parenchymal phase, and excretion phase) with monophase infusion of iomeprole (Iomeron® 350 or 400, Bracco Imaging, Milano, Italy) at a dose of 350 or 400 mg of iodine per milliliter. A flowchart is shown in Figure 1.

[0039] Clinical and biological data Sex, age, weight, height, and serum creatinine levels were collected from medical records.

[0040] GFR measurement using iohexole clearance: After injecting a 5 mL bolus of iohexol (300 mg / L Omnipaque®; GE Healthcare, France) and an equilibrium period (the time required for the tracer to disperse into the extracellular compartment), blood and urine samples were collected over 4 to 6 consecutive clearance periods. The inventors performed six 30-minute periods after a 90-minute equilibrium period, followed by four 40-minute periods after a 120-minute equilibrium period, until July 2019. The concentrations of iohexol in serum and urine were measured as previously described (Cavalier E As et al. (

[12] ), GFR was determined by high-performance liquid chromatography (HPLC). The measured GFR (mGFR) was the average of 4 to 6 clearance period values ​​calculated as U × V / P, where U is the concentration of iohexol in the urine collected during that period, V is the urinary flow rate during that period, and P is the serum concentration of iohexol in the intermediate period. Considering the negative bias of this GFR measurement method (Seegmiller JC et al. (

[13] , Stehle T et al. (

[14] )), the following correction was used: mGFR = 1.15 × (iohexol (iohexol urinary clearance) + 1.3 (Stehle T et al. (

[14] )). In cases of irregular or incomplete urination, or urinary incontinence, mGFR was calculated using the Brochner-Mortensen corrected model for the lost early compartment (Brochner-Mortensen JA (

[15] )) with iohexol plasma clearance determined from the plasma elimination curve.

[0041] GFR measurement using iomeprole clearance evaluated by CT urography (CT-mGFR): CT-mGFR was assessed using the same U×V / P formula used to determine iohexol urinary clearance, which divides the amount of iomeprole excreted through the urinary system during a given period by the mean serum iomeprole concentration during the same period. Blood and urine concentrations of iomeprole were assessed by attenuation measurements (Hounsfield units, HU) in different regions of interest. The periods were different phases. These data were derived from acquisition times. These data were acquired for all patients and phases within the DICOM 0008-0032 "Acquisition Time" header, which represents the time acquisition began. Manual segmentation of the bladder, upper urinary tract, and kidneys was performed using Advantage Windows software (Advantage Window v4.7; GE Healthcare, Buc, France) with different thresholds depending on the CT phase, and then manually finalized. For the simple and portal venous phases, only the lower limit was set to 0HU to exclude fat pixels. For the excretion phase, specific thresholds were adapted for each patient based on visual analysis to reduce extraurinal pixels as much as possible. Additionally, to avoid overlap in segmentation, the lower threshold used for the upper excretion tract was used as the upper threshold for kidney segmentation. The urinary excretion rate of iomeprole between the arterial and excretion phases (U×V, expressed as HU / min) was calculated from the urinary excretion of iomeprole into the bladder (Uexcr-bladder), into the upper excretory tract (renal calyces, pelvis, ureters) (Uexcr-tract), and into the renal tubules (Uexcr-tubule): U×V = Uexcr-bladder + Uexcr-tract + Uexcr-tubule. Uexcr-bladder was calculated by multiplying the bladder volume in the elimination phase (bladder-Volume) by the difference between the mean CT attenuation of the bladder in the elimination phase (HU-bladder-excr) and the CT attenuation of urine in the bladder in the simple phase (HU-bladder-simple) and then dividing by the period between the elimination phase and the arterial phase (period): Uexcr-bladder = bladder-volume × (HU-bladder-excr - HU-bladder-simple) / period. When the bladder is not included in the simple phase, urine CT attenuation can be measured in the renal parenchymal phase, and urine density in the renal parenchymal phase is slightly higher than density in the simple phase, but there is no clinical consequence in CT-mGFR calculation. The Uexcr-path was determined in the same way by studying the upper excretory tract (renal calyces, pelvis, ureters) instead of the bladder.Uexcr-tubule was calculated by multiplying the volume of both kidneys (kidney-volumes) by the difference between the mean renal CT attenuation in the excretion phase (HU-kidney-excr) and the mean renal CT attenuation in the simple phase (HU-kidney-simple) and then dividing by the period: Uexcr-tubule = kidney-volumes × (HU-kidney-excr - HU-kidney-simple) / period. The denominator of the U × V / P formula was the serum iomeprole concentration calculated at the midpoint of the period between the arterial and excretion phases. In each phase, the difference between the aortic CT attenuation and the CT attenuation in the simple phase was used as a substitute for the serum iomeprole concentration. By considering the aortic CT attenuation in the simple phase, hematocrit was taken into account in the measurement of iomeprole, and therefore an equivalent of the serum assay rather than the whole blood assay was provided (Black DF et al. (

[16] )). The decrease in serum iomeprole concentration during the period between the arterial and excretion phases (including both its distribution in the extracellular compartment and its urinary excretion by glomerular filtration) follows an exponential curve; therefore, this decrease was modeled by linear regression after converting each serum concentration equivalent (in HU) to a natural logarithm. From this linear regression, the serum concentration at half-life was estimated. Each measurement was performed by one senior radiologist. An example of CT-mGFR calculation from a patient is provided below (step-by-step explanation of CT-mGFR calculation), see section C below. An online calculator is also available at the following web address: https: / / paul-bssr-app-streamlit-gfr-streamlit-app-6uzfvr.streamlit.app /

[0042] Step-by-step explanation of CT-mGFR calculation: Example using values ​​from a patient's CT scan The formula for calculating CT-mGFR is: (Uexcr-bladder (A) + Uexcr-tract (B) + Uexcr-tubule (C)) / Serum iomeprole concentration in the midterm (D) A) Uexcr - Bladder: Excretion of iomeprole into the bladder 3D segmentation of the bladder in the simple phase: mean decay 23.9 HU 3D segmentation of the bladder during the elimination phase: volume 161 mL, mean decay 445.6 HU 1. Bladder volume during the elimination phase: 161 mL 2. Time between arterial phase and excretion phase: 9.47 minutes 3. Mean CT attenuation of the bladder during the elimination phase (HU-bladder-excr): 445.6HU 4. Mean CT attenuation of urine in the bladder during the simple phase (HU-bladder-simple): 23.9 HU →Uexcr-bladder=(445.6-23.9)×161 / 9.47=7169.3HU×mL / min B) Uexcr- tract: Urinary excretion of iomeprole into the upper excretory tract (renal calyces, pelvis, ureter). 3D segmentation of the bladder in the simple phase: mean decay 23.9 HU 3D segmentation of the upper urinary tract during the excretory phase: volume 15.7 mL, mean decay 738.2 HU 1. Volume of the excretory tract during the excretory phase: 15.7 mL 2. Time between arterial phase and excretion phase: 9.47 minutes 3. Mean CT attenuation of the excretory tract during the excretory phase (HU-excr-tract): 738.2HU 4. Mean CT attenuation of urine in the bladder during the simple phase (HU-bladder-simple): 23.9 HU →Uexcr-Route=(738.2-23.9)×15.7 / 9.47=1184.2HU×mL / min C) Uexcr - Renal tubule: Urinary excretion of iomeprole into the renal tubules 3D segmentation of the kidney in the simple phase: volume 387 mL, mean decay 34.8 HU 3D segmentation of the kidney during the excretion phase: mean decay 97.7 HU 1. Total volume of both kidneys: 387 mL 2. Time between arterial phase and excretion phase: 9.47 minutes 3. Mean CT attenuation of the kidney during the excretion phase (HU-kidney-excr): 97.7HU 4. Mean CT attenuation of the kidney in the simple phase (HU-kidney-simple): 34.8 HU →Uexcr - renal tubule = (97.7 - 34.8) × 387 / 9.47 = 2570.5 HU × mL / min D) Serum iomeprole concentration in the intermediate phase between the arterial and excretion phases Aortic CT attenuation in the simple phase: 46 HU Aortic CT attenuation in the arterial phase: 256.2 HU Aortic CT attenuation in the renal parenchymal phase: 134.3 HU Aortic CT attenuation during the excretion phase: 92.8 HU 1. Serum iomeprole concentration evaluated in the arterial phase = 256.2 - 46 = 210.2 HU 2. Serum iomeprole concentration evaluated in the renal parenchymal phase = 134.3 - 46 = 88.3 HU 3. Serum iomeprole concentration evaluated during the excretion phase = 92.8 - 46 = 46.8 HU 4. Natural logarithmic conversion of three serum iomeprole concentration values i. Ln (serum iomeprole concentration assessed in the arterial phase) = Ln(210.2) = 5.35 ii. Ln (serum iomeprole concentration assessed in the renal parenchymal phase) = Ln(88.3) = 4.48 iii. Ln (serum iomeprole concentration evaluated during the excretion phase) = Ln(46.8) = 3.85 5. Determine the linear regression equations of these three logarithmic values ​​as a function of time (for this patient, arterial phase: 0 mins, renal parenchymal phase: 0.77 mins, and excretion phase: 9.47 mins): Ln(imeprole) = 4.98 - 0.123 × time (mins) 6. Determine the serum concentration of iomeprole (at HU) during the intermediate phase between the arterial and excretion phases: Ln(iomeprole intermediate phase) = 4.98 - 0.123 × 9.47 / 2 = 4.396 → Iomeprole medium-term = Exp(4.396) = 81.1 HU

[0043] CT-mGFR calculation: Therefore, in this example, CT-mGFR is: (Uexcr-bladder(A)+Uexcr-tract(B)+Uexcr-renal tubule(C)) / Iomeprol mid-stage(D) =(7169.3+1184.2+2570.5) / 81.1=134.2ml / min Next, CT-mGFR can be adjusted relative to body surface area (BSA). That is the case. The patient's weight is 99 kg and height is 175 cm => BSA is 2.18 m according to Mosteller's formula. 2 This is the result. CT-mGFR = 134.2 / BSA × 1.73 = 106.0 ml / min / 1.73m 2

[0044] Statistical analysis: For continuous variables, the median and interquartile range (IQR) are used as needed. Alternatively, the values ​​were expressed as the mean and standard deviation (SD). The inventors analyzed the relationship between CT-mGFR and iohexol urinary clearance using Passing-Bablok regression and calculated the slope, intercept, and their 95% confidence intervals (95% CI) (Passing H et al. (

[17] )). The inventors evaluated the performance of CT-mGFR compared to mGFR by determining mean bias as the mean difference between CT-mGFR and mGFR, precision as the standard deviation of the bias, and accuracy as the percentage of CT-mGFRs that fall within 10%, 20%, and 30% of mGFR. The inventors provided a visual representation of agreement using a Bland-Altman plot (Bland JM, Altman DG (

[18] )). Agreement between GFR determination methods was also evaluated by Lin's concordance correlation coefficient (CCC) (Lin LI (

[19] )). Using plasma creatinine measured routinely at the same time as Alan, CKD-EPI 2021The same analysis was performed to evaluate the performance of eGFR determined from formula (Inker LA(

[20] )). The inventors used the Pitman test to compare the variances of correlated samples: CT-mGFR vs CKD-EPI 2021 The accuracy of the methods was compared. To compare accuracy, the inventors used the McNemar test. Statistical analysis was performed using Microsoft® Excel and XLSTAT® software (Addinsoft 2021).

[0045] result: Clinical characteristics: The study included 75 individuals out of 199 kidney donor candidates who underwent GFR measurement using iohexol clearance between July 2016 and October 2022. Main reasons for non-inclusion: The reasons for the absence of CT urography available through the image storage and communication system were either the lack of available CT urography (n=52) or the performance of CT scans without an excretion phase (n=61) (Figure 1). The demographic and morphological characteristics of the subjects are described in Table 1.

[0046] [Table 1]

[0047] CT urography contrast protocol: Table 2 shows the details of the CT urography equipment.

[0048] [Table 2]

[0049] Seventy CT urography procedures were performed in the inventors' department using GE Discovery CT® (n=48) or GE Revolution CT® (n=22), and five CT urography procedures were performed using Siemens SOMATOM Definition AS® (n=1), Toshiba Aquilion PRIME® (n=1), GE optima CT540® (n=2), or Philipps Ingenuity CT® (n=1) devices. The procedure was performed externally. The X-ray tube voltage was mainly 120kVp, and the same X-ray tube voltage was used between different acquisitions. The slice thickness was 1.25mm. Iterative reconstruction was applied to 64 patients using TrueFidelity Deep Learning Image Reconstruction. Reconstruction) (TF-H GE® registered trademark) was applied to 11 people. Softfill The bolus kernel was applied to all acquisitions. All patients received iomeprol at 350 mg / L, except for 7 patients who received iomeprol at 400 mg / L. The mean administered dose of iomeprol was 948.5 ± 177.4 mg / Kg (Table 2), and the maximum and minimum administered doses were 676.4 mg / Kg to 1350 mg / Kg. The iomeprol injection rate was 2.5 to 3.5 ml / sec, depending on the quality of venous access, except for externally performed CT urograms (n = 5) where the injection rate was unknown. Arterial phases obtained 20 seconds (n = 30) or 6 seconds (n = 38) after the attenuation increase in the abdominal aorta reached predetermined thresholds of 100 HU and 250 HU, respectively, were used for 68 CTs performed at the inventors' facility, using bolus tracking software (Smartprep, GE Healthcare, WI, USA). For the remaining 5 patients, arterial phase delay was not available. Only 2 of the patients in this study received furosemide. The median time between the arterial and renal parenchymal phases restored from DICOM data was 47 seconds [IQR: 44, 50] (min: 31, max: 74). The median time between the arterial and excretory phases was 9.5 minutes [IQR: 9.3, 9.7] (min: 6.2, max 13.3).

[0050] Measurement of GFR using iomeprol clearance evaluated by CT urogram (CT-mGFR): The mean and median values of different CT attenuations and volumes used to calculate CT-mGFR are listed in Table 2. The mean CT-mGFR was 100.9 ± 19.5 ml / min / 1.73m 2 (minimum = 60.8, maximum = 174.0), and was not statistically different from the mGFR of 99.7 ± 19.1 ml / min / 1.73m 2 (minimum = 59.9, maximum = 140.2) (paired t-test, p-value: 0.47). The relationship between CT-mGFR and mGFR obtained by Passing-Bablok regression is shown in Figure 2: the regression line was very close to the identity line. The agreement between CT-mGFR and mGFR is also shown as a Bland Altman plot (Figure 2): the mean bias was 1.1 ml / min / 1.73m2 The values ​​were (-1.9, 4.1) (Table 3). The accuracy within 10%, 20%, and 30% (AW) was 61.3% (95% CI: 50.3, 72.4), respectively. The percentages were 88.0% (95% CI: 80.7, 95.4) and 100%.

[0051] [Table 3]

[0052] The accuracy of CT-mGFR did not appear to be affected by patient ethnicity or hydration status (data not shown), nor by the dose of iomeprole administered (data not shown), the model or brand of the CT scan (data not shown), the time interval between the arterial and excretion phases (data not shown), the CT tube voltage (data not shown), the CT reconstruction modality (data not shown), or the procedure for acquiring the arterial phase (data not shown). Two patients who received furosemide had reasonably good outcomes (CT-mGFR was -8% and +12% of mGFR).

[0053] CT-mGFR is CKD-EPI 2021 It exhibited better accuracy and precision than the previous method (Table 3, Figure 2).

[0054] Intra-observer reproducibility of CT-mGFR: Intra-observer reproducibility for CT-mGFR was determined from 30 patients randomly selected from the study population. Bland-Altman (Figure 4) shows unbiased pairwise measurements with excellent agreement. The accuracy within 10% was 100%, and the Lin-coordinate correlation coefficient was 0.989 (95% CI: 0.978, 0.994).

[0055] Consideration: Based on the results of our research, we have proposed a novel method for measuring GFR using CT-mGFR, a measurement of contrast agent clearance such as iomeprole, evaluated by CT urography, enabling accurate and reproducible evaluation of GFR in living kidney donor candidates.

[0056] It has been suggested that a GFR measurement method is considered to have sufficient accuracy if the median bias is less than 5% compared to the standard method, at least 80% of the measurements are within ±30% of the reference measurement, and at least 50% are within ±10% (Soveri I et al.). al. (

[21] ). Iomeprole is a low-viscosity, low-osmolarity, nonionic, water-soluble, iodinating contrast agent. Its molecular weight of 777.09 daltons is slightly smaller than that of iohexol (821.1 Da) or iotalamate (809.1 Da), two iodinating contrast agents widely used in GFR measurement. Furthermore, iomeprol does not bind to plasma proteins to a measurable degree (Lorusso V et al. (

[22] ). These chemical properties make iomeprol a potentially ideal exogenous marker for measuring GFR, namely, it diffuses freely into extracellular volume, is not metabolized, does not bind to plasma proteins, is freely filtered and therefore eliminated only by the kidney, and is not secreted or reabsorbed into the renal tubules. Pharmacokinetic studies have shown that after bolus infusion of iomeprol, its plasma concentration decreases bi-exponentially (the first slope corresponds to its diffusion in extracellular volume and its renal clearance, and the second slope corresponds to its renal clearance only), extrarenal clearance is negligible, and there is a very good correlation between its clearance and inulin clearance (Lorusso V et al. et al. (

[23] ).

[0057] The present invention's method for measuring GFR based on CT scans is accurate and, provided that the simple phase, arterial phase, renal parenchymal phase, and excretion acquisition phase are available, can be used in conjunction with CT urography data obtained from routine clinical practice in an opportunistic value-added CT imaging approach. Since CT-mGFR is a measure of exogenous tracer (iomeprole) clearance, it is accurate regardless of the patient's lineage. In this study population, there was some patient-to-patient variation in the dose of infused iomeprole, but this did not hinder the efficiency of our method, as the urinary clearance measurement of exogenous tracer is independent of the dose of the administered tracer. Patient-to-patient variability in the acquisition time of the excretion phase also did not hinder the effectiveness of our method: urinary clearance of exogenous tracer. When measuring GFR, the key is not to strictly adhere to extremely precise timing, but to record this sampling timing with great accuracy, which is done automatically during the CT scan, and these image acquisition times are recorded in the DICOM header. This allows the CT scan to avoid potential inaccuracies associated with errors in recording blood or urine collection times, which can occur with standard GFR measurement methods. It also eliminates inaccuracies associated with insufficient urination or uncollected urine (which is also a major limitation on the accuracy of GFR measurements using urine clearance procedures). CT-mGFR also has the advantage of being much quicker and less cumbersome than GFR measured using exogenous tracer clearance. Furthermore, there is no additional cost when performed on patients undergoing CT scans as part of medical follow-up, such as in the evaluation of kidney donor candidates or nephrectomy for precancerous conditions. Renal volume measurement and renal augmentation can also provide information about the distribution of function between two kidneys, i.e., information not provided by GFR measurement based on exogenous tracer clearance. Finally, it should be noted that patient-to-patient variability in CT scan brand and model, CT tube voltage, and reconstruction modality did not appear to affect the performance of the measurement of this invention.

[0058] In conclusion, GFR can be accurately measured from CT urography performed in a routine clinical setting without any specific acquisition protocol other than performing the simple phase, arterial phase, renal parenchymal phase or portal venous phase, and excretion phase.

[0059] Example 2: Contrast agent clearance evaluated by CT urography to measure GFR in subjects with low GFR. Chronic kidney disease (i.e., estimated GFR < 60 ml / min / 1.73 m²) 2 In patients having (and / or other characteristics of chronic kidney disease), certain embodiments of the method of the present invention may be implemented to avoid or reduce overestimation of the measured GFR compared to healthy individuals.

[0060] In fact, overestimation was observed in an average of 12% of patients with chronic kidney disease.

[0061] The inventors have shown that this is due to the fact that the tubular compartment is overestimated in the calculation of the urinary excretion rate of the contrast product between the arterial phase and the excretion phase.

[0062] Accordingly, the inventors have developed embodiments of the method of the present invention that are more suitable for patients with low GFR, including cortical segmentation. This method has minimal impact on healthy individuals and can be used in healthy individuals as well.

[0063] method Research sample: This retrospective cross-sectional study involved GFR measurements by iohexol clearance at the inventors' facility from July 2016 to April 2024, with creatinine-based eGFR and / or cystatin C-based eGFR levels below 60 ml / min / 1.73m². 2Data was used from all patients who were less than CKD and underwent CT urography within 3 months before or after GFR measurement. CT urography had to be available in the hospital's image storage and communication system and had to include the following four phases, namely the simple phase, arterial phase, renal parenchymal phase, and excretion phase, using the same X-ray tube voltage between different acquisitions. There were no exclusion criteria. GFR performance measured by CT urography in CKD patients was compared to GFR performance measured by the same method in 75 healthy individuals from the original study. The French Ethics Committee for the Research in Medical Imaging The Institutional Review Board of CERIM approved this study (No. CRM-2403-402), and informed consent was obtained from the patients.

[0064] GFR measurement using iohexole clearance: Iohexol clearance was measured as described above in Example 1.

[0065] GFR measurement using contrast agent clearance evaluated by CT urography: Senior nephrologists performed segmentation of CKD patients and healthy individuals using 3D Slicer 5.4.0 software. To assess inter-observer reproducibility in CKD patients, senior radiologists who had previously measured GFR from CT urography in healthy individuals also determined CT-measured GFR in CKD patients using Advantage Windows software (version 4.7, GE Healthcare), as in Example 1. Inter-observer agreement in the previously unassessed normal GFR range was determined using CT-measured GFR values ​​previously calculated by senior radiologists in living kidney donors.

[0066] The CT-measured GFR was calculated as in Example 1. The inventors also evaluated the CT-measured GFR calculation after subtracting the portion of renal cortical enhancement in the excretion phase due to cortical vascular compartments. Details of the segmentation and calculation steps required for this modified method for determining the tubular excretion rate of contrast agent are provided in Figure 5.

[0067] Statistical analysis: Continuous variables were expressed as medians, along with interquartile ranges (IQR) or mean ± standard deviation (SD), as needed. The inventors evaluated the performance of CT-measured GFR based on relative bias, defined as 1 / CT-mGFR divided by the measured GFR (mGFR); precision, defined as the distance between the first and third quartiles of bias; and accuracy, defined as the proportion of patients with CT-measured GFR falling within 10%, 20%, and 30% of mGFR. A Bland-Altman plot was used to show the agreement between CT-measured GFR and mGFR. Inter-observer agreement was also evaluated using the Lin concordance correlation coefficient. The precision of CTmGFR in CKD patients was compared to the precision of CTmGFR in healthy individuals using an F-test for variance comparison, and accuracy was compared using Fisher's exact test. This was done in the CKD patient group first, then in the healthy individual group. P<0.05 was considered statistically significant. Statistical analysis was performed using Microsoft Excel and XLSTAT software (version 2024.1.0, Addinsoft).

[0068] result Characteristics of CKD patients This study included 28 patients (Figure 4), 10 women and 18 men. The mean age was 68.7 ± 16.4 years, with 5 patients aged 85-90 years. The mean BMI was 25.5 kg / m2 ± 4.2, and 4 patients were obese (BMI > 30). The most common reason for measuring GFR was to predict postoperative GFR in CKD patients scheduled to undergo nephrectomy or nephroureterectomy due to cancer. The mean GFR based on iohexol clearance was 46.0 ml / min / 1.73m2 2 The result was ±15.8. All patient characteristics are shown in Table 4.

[0069] CT urography parameters All CT scans except one were performed on a GE HealthCare Revolution machine. For 22 patients, the CT tube voltage was in the range of 100–120 kVp. Six patients underwent dual-energy CT urography with monochromatic image reconstruction at 40 keV (80–140 kVp). The slice thickness was 1.25 for 26 of the 28 patients. Iodized contrast agents were used: iomeprole for 18 patients, iobitridol for 6 patients, and iodixanol for 2 patients. In contrast, this was unknown to two patients who underwent CT urography at an external facility (Table 4).

[0070] [Table 4]

[0071] Comparison of GFR measured using contrast agent clearance and iohexol clearance evaluated by CT urography. When CT-mGFR was calculated under the assumption that all renal parenchymal enhancement in the excretion phase originated from the tubular compartment, it overestimated mGFR by 11.6% (95% CI: 5.5, 17.7) compared to mGFR calculated by iohexol clearance (Table 5, Figure 6). Compared to CT-mGFR calculated in living kidney donor candidates, CT-mGFR from CKD patients was less accurate (95% CI: 67.9%, P-value: 0.06, given the limited statistical power due to the small number of patients), and the portion of renal cortical enhancement in the excretion phase originating from the cortical vascular compartment was also less accurate. When subtracted from the CT-mGFR calculation, the values ​​became very high at 100%, 92.9% (95% CI: 83.3, 100), and 50% (95% CI: 31.5, 68.5), and statistically indistinguishable from those seen in healthy subjects (100%, 89.3% (95% CI: 82.4, 96.3), and 54.7% (95% CI: 43.3, 65.9), with p-values ​​of 1, 0.6, and 0.7, respectively). At accuracy within 30%, 20%, and 10%, CT-mGFR was unbiased (mean bias: 2.9% (-1.9, 7.7)). The effect of subtracting cortical potentiation from vascular compartments when calculating CT-mGFR in healthy individuals was not significant, there was no bias for iohexol clearance (mean bias: -2.2% (95% CI -5.0, 0.05)), and the two methods for calculating tracer tubular excretion remained very good in terms of accuracy (Table 5).

[0072] [Table 5]

[0073] Inter-observer reproducibility of cortical-adjusted CT-measured GFR in CKD patients Inter-observer agreement was assessed by the Lin concordance correlation coefficient at 0.99 (95% CI: 0.97, 0.99), regardless of whether the CT-measured GFR was determined with or without consideration of cortical potentiation due to its vascular compartment. In healthy individuals, the values ​​for CT-measured GFR determined with and without cortical adjustment were 0.92 (95% CI: 0.88, 0.95) and 0.91 (95% CI: 0.87, 0.94), respectively (the values ​​were slightly lower due to the higher range of GFR). The Bland-Altman expression showed that there was no bias between the two assessors in CKD patients, as there was for healthy individuals, and that the lower and upper limits of the agreement interval were very close in the two groups (Figure 7).

[0074] Consideration: There is a need to develop a rapid and reproducible method for measuring GFR that can be used on a large scale in clinical practice. In the examples, the inventors have developed a novel method for accurately measuring GFR from quaternary multicolor CT urography performed as part of routine treatment in healthy individuals. A method was developed. The primary objective of the inventors' novel research was to evaluate the performance of this CT urography-based method for measuring GFR in patients with chronic kidney disease (CKD). CT-mGFR was unbiased (mean bias: 2.9% (95% CI: -1.9, 7.7)) and accurate compared to iohexol clearance (standard method), under the condition that the portion of renal cortical enhancement in the excretion phase due to contrast agent in the vascular compartment was subtracted from the CT-mGFR calculation (precision within 30%, 20%, and 10%, respectively: 100%, 92.9% (95% CI 83.3, 100), and 50% (31.5, 68.5)). In healthy individuals with normal GFR, CT-mGFR was unbiased and highly accurate, regardless of whether the cortical vascular compartment was included in or subtracted from the CT-mGFR calculation. The inter-observer agreement of CT-mGFR obtained using different segmentation software was superior in CKD patients, with a Lin-coordinate correlation coefficient of 0.99 (95% CI: 0.97, 0.99).

[0075] Conventional methods for measuring GFR from CT scans have used pharmacokinetic models such as Patlak's model ([7]), required specific dynamic acquisitions, and yielded imperfectly accurate results [4, 5]. More recently, approaches have been developed to measure iodized contrast agent clearance by dividing the contrast agent filtration rate by the plasma concentration of the iodized contrast agent, but these still have limitations such as the need to use specific CT acquisition procedures, whether dynamic or not, the need to perform hematocrit blood tests at the time of CT, and results that are not always optimally accurate (Yuan X et al. ([2]), You S et al. ([3]). Furthermore, these studies included very few CKD patients: in Yuan et al.'s study, only two patients had a plasma clearance of technetium-99m diethylenetriaminepentaacetic acid of less than 60 ml / min (Yuan X et al. ([2]). In the study by You, Ma, and Zhang, where CT-mGFR was divided into single-renal GFR, only 5 out of 36 patients had a single-renal GFR of less than 30 ml / min (You S et al. ([3])). Although the number of patients in our study was limited, these are the first promising results for the future use of CT-urography in a value-added opportunistic imaging approach for measuring GFR in CKD patients.

[0076] Our results demonstrate that our method for measuring GFR by CT scan can be used with different iodinating contrast agents such as iomeprole, iobitridol, and iodixanol. Furthermore, pharmacokinetic studies show that these molecules, with molecular weights of 835 g / mol and 1550 g / mol, are eliminated almost exclusively by urinary excretion, more specifically by glomerular filtration (Svaland MG et al. (

[25] ), Spencer CM, Goa KL (

[26] )). Similarly, since 6 out of 28 patients underwent monochromatic CT scans, this demonstrates that our CT scan-based GFR measurement method can be used with spectral CT scans.

[0077] In conclusion, our method for measuring GFR from CT-urography performed as part of routine treatment is effective in patients with chronic kidney disease (CKD), provided that renal cortical enhancement during the excretion phase, due to the presence of tracers in the cortical vascular compartments, is subtracted from the calculation of iodized contrast agent clearance. Its application in routine clinical practice is primarily related to the field of urological oncology (e.g., prediction of GFR after nephrectomy, decision on whether or not to administer cisplatin, and calculation of carboplatin dosage based on the Calvert formula using mGFR rather than eGFR).

[0078] List of References 1.Ebert N, Bevc S, Bokenkamp A, et al.Assessment of kidney function: clinical indicator ations for measured GFR.Clinical Kidney Journal.2021;14(8):1861-1870.doi:10.1093 / ckj / sfab042. 2.Yuan X,Zhang J,Tang K,et al.Determination of Glomerular Filtration Rate with CT Measurement of Renal Clearance of Iodinated Contrast Material versus 99m Tc-DTPA Dynamic Imaging「Gates」Method:A Validation Study in Asymmetrical Renal Disease.Radiology.2017;282(2):552-560.doi:10.1148 / radiol.2016160425. 3.You S,Ma X,Zhang C,et al.Determination of single-kidney glomerular filtration rate(GFR)with CT urography versus renal dynamic imaging Gates method.Eur Radiol.2018;28(3):1077-1084.doi:10.1007 / s00330-017-5061-z. 4.Hackstein N,Puille MF,Bak BH,Scharwat O,Rau WS.Measurement of single kidney contrast media clearance by multiphasic spiral computed tomography:preliminary results.Eur J Radiol.2001;39(3):201-208.doi:10.1016 / s0720-048x(01)00323-0. 5.Hackstein N,Wiegand C,Rau WS,Langheinrich AC.Glomerular filtration rate measured by using triphasic helical CT with a two-point Patlak plot technique.Radiology.2004;230(1):221-226.doi:10.1148 / radiol.2301021266. 6.Jeong S,Park SB,Chang IH,et al.Estimation of renal function using kidney dynamic contrast material-enhanced CT perfusion:accuracy and feasibility.Abdom Radiol.2021;46(5):2045-2051.doi:10.1007 / s00261-020-02826-7. 7.Patlak CS,Blasberg RG,Fenstermacher JD.Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.J Cereb Blood Flow Metab.1983;3(1):1-7.doi:10.1038 / jcbfm.1983.1. 8.Aydin F,Gungor F,Cengiz AK,et al.Comparison of glomerular filtration rate measurements with the two plasma sample and single plasma sample,gamma camera Gates,creatinine clearance,and prediction equation methods in potential kidney donors with normal renal function.Nucl Med Commun.2008;29(2):157-165.doi:10.1097 / MNM.0b013e3282f1bbde. 9.Itoh K.Comparison of methods for dete rmination of glomerular filtration rate:Tc-99m-DTPA renography,predicted creatinine clearance method and plasma sample method.Ann Nucl Med.2003;17(7):561-565.doi:10.1007 / BF03006669. 10.Kumar M,Arora G,Damle N,et al.Comparison between two-sample method with 99m Tc-diethylenetriaminepentaacetic acid,Gates’ method and estimated glomerular filtration rate values by formula based methods in healthy kidney donor population.Indian J Nucl Med.2017;32(3):188.doi:10.4103 / ijnm.IJNM_17_17. 11.Lentine KL,Kasiske BL,Levey AS,et al.KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors.Transplantation.2017;101(8S):S7-S105.doi:10.1097 / TP.0000000000001769. 12.Cavalier E,Rozet E,Dubois N,et al.Performance of iohexol determination in serum and urine by HPLC:validation,risk and uncertainty assessment.Clin Chim Acta.2008;396(1-2):80-85.doi:10.1016 / j.cca.2008.07.011. 13.Seegmiller JC,Burns BE,Schinstock CA,Lieske JC,Larson TS.Discordance Between Iothalamate and Iohexol Urinary Clearances.Am J Kidney Dis.2016;67(1):49-55.doi:10.1053 / j.ajkd.2015.08.020. 14.Stehle T,El Karoui K,Sakka M,et al.Creatinine clearance after cimetidine administration in a new short procedure:comparison with plasma and renal clearances of iohexol.Clinical Kidney Journal.2020;13(4):587-596.doi:10.1093 / ckj / sfz087. 15.Brochner-Mortensen J.A Simple Method for the Determination of Glomerular Filtration Rate.Scandinavian Journal of Clinical and Laboratory Investigation.1972;30(3):271-274.doi:10.3109 / 00365517209084290. 16.Black DF,Rad AE,Gray LA,Campeau NG,Kallmes DF.Cerebral venous sinus density on noncontrast CT correlates with hematocrit.AJNR Am J Neuroradiol.2011;32(7):1354-1357.doi:10.3174 / ajnr.A2504. 17.Passing H,Bablok null.A new biometrical procedure for testing the equality of measurements from two different analytical methods.Application of linear regre ssion procedures for method comparison studies in clinical chemistry,Part I.J Clin Chem Clin Biochem.1983;21(11):709-720.doi:10.1515 / cclm.1983.21.11.709. 18.Bland JM,Altman DG.Statistical methods for assessing agreement between two methods of clinical measurement.Lancet.1986;1(8476):307-310. 19.Lin LI.A concordance correlation coefficient to evaluate reproducibility.Biometrics.1989;45(1):255-268. 20.Inker LA,Eneanya ND,Coresh J,et al.New Creatinine-and Cystatin C-Based Equations to Estimate GFR without Race.N Engl J Med.2021;385(19):1737-1749.doi:10.1056 / NEJMoa2102953. 21.Soveri I,Berg UB,Bjork J,et al.Measuring GFR:A Systematic Review.American Journal of Kidney Diseases.2014;64(3):411-424.doi:10.1053 / j.ajkd.2014.04.010. 22.Lorusso V,Luzzani F,Bertani F,Tirone P,de Haen C.Pharmacokinetics and tissue distribution of iomeprol in animals.Eur J Radiol.1994;18 Suppl 1:S13-20.doi:10.1016 / 0720-048x(94)90090-6. 23.Lorusso V,Taroni P,Alvino S,Spinazzi A.Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis.Invest Radiol.2001;36(6):309-316.doi:10.1097 / 00004424-200106000-00002. 24.Stehle T,Wei F,Brabant S,et al.Glomerular Filtration Rate Measured Based on Iomeprol Clearance Assessed at CT Urography in Living Kidney Donor Candidates.Radiology.2023;309(3):e230567.doi:10.1148 / radiol.230567. 25.Svaland MG,Haider T,Langseth-Manrique K,Andrew E,Hals PA.Human pharmacokinetics of iodixanol.Invest Radiol.1992;27(2):130-133.doi:10.1097 / 00004424-199202000-00007. 26.Spencer CM,Goa KL.Iodixanol:A Review of its Pharmacodynamic and Pharmacokinetic Properties and Diagnostic Use as an x-Ray Contrast Medium.Drugs.1996;52(6):899-927.doi:10.2165 / 00003495-199652060-00013.

Claims

1. A method for ex vivo measurement of the glomerular filtration rate (GFR) of a subject who has been administered a contrast agent and has undergone computed tomography (CT) or magnetic resonance imaging (MRI) including the excretion phase, simple phase, arterial phase, and renal parenchymal phase or venous portal phase, A method comprising the steps of calculating the clearance of the contrast agent from CT or MRI data using manual, automatic, or semi-automatic segmentation software, and thereby obtaining the measured GFR.

2. The method according to claim 1, wherein the contrast agent is an ideal GFR marker that is iodized or uniodized.

3. The method according to claim 1 or 2, wherein contrast agent clearance is calculated by dividing the urinary excretion rate of the contrast agent between the arterial phase and the excretion phase by the calculated serum concentration of the contrast agent in the intermediate phase.

4. The method according to claim 3, wherein the urinary excretion rate of the contrast agent between the arterial phase and the excretion phase is the sum of the urinary excretion of the contrast agent into the bladder, the urinary excretion of the contrast agent into the upper excretory tract, and the urinary excretion of the contrast agent into the renal tubules.

5. The method according to claim 4, wherein the urinary excretion of the contrast agent into the renal tubules is calculated by multiplying the volume of both kidneys by the difference between the mean renal decay in the simple phase and the mean renal decay in the simple phase, and then dividing by the period.

6. The method according to claim 4, wherein the urinary excretion of the contrast agent into the renal tubules is the sum of the urinary excretion of the contrast agent into the renal medulla and the urinary excretion of the contrast agent into the renal cortex.

7. - The urinary excretion of the contrast agent into the renal medulla is calculated by multiplying the volume of the renal medulla by the difference between the average CT attenuation of the kidney in the excretion phase and the average attenuation of the kidney in the simple phase, and then dividing by the period. The method according to claim 6, wherein the urinary excretion of the contrast agent to the renal cortex is calculated by multiplying the volume of the renal cortex by the result of subtracting the CT attenuation of the kidney in the simple phase from the average CT attenuation of the kidney in the excretion phase, further subtracting the cortical CT attenuation from the vascular compartment in the excretion phase, and then dividing by the time between the arterial phase and the excretion phase.

8. The method according to claim 3, wherein a specific region of a CT scan or MRI scan is segmented at different times in order to determine the urinary excretion rate of the contrast agent.

9. The method according to claim 3, wherein the intermediate serum contrast agent concentration is estimated from linear regression or polynomial regression after each intermediate value of the serum concentration equivalent is converted to a natural logarithm.

10. The method according to any one of claims 1 to 9, wherein the calculation step is performed automatically using software developed from an algorithm developed by artificial intelligence or other means.

11. The method according to any one of claims 1 to 10, wherein the excretion phase comprises the renal parenchyma, the upper renal excretory system, and the bladder; the simple phase comprises the renal parenchyma and optionally the bladder; the arterial phase comprises either a single slice of the aorta or the entire height of the kidney; and the renal parenchymal phase or portal venous phase, if not included in the simple phase, comprises at least one single slice of the aorta together with the bladder.

12. The method according to any one of claims 1 to 11, wherein the concentration of the contrast agent is determined in CT by a method other than Hunsfield unit counting, for example, by direct quantification of the contrast agent by spectral imaging in CT with or without photon counting or spectral CT.

13. The method according to any one of claims 1 to 12, wherein the measurement value of the urinary excretion of the contrast agent in the bladder is determined based on the portion of the bladder or the total volume of the bladder that is enhanced by the contrast agent.

14. The method according to any one of claims 1 to 13, wherein the volume or a single slice of the aorta is used to measure the CT density or MRI signal of the aorta.

15. The method according to any one of claims 1 to 14, wherein the contrast agent is an iodized contrast agent selected from, for example, iomeprole, iobitridol, and iodixanol.

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