There is an unmet need for tomographic imaging techniques capable of pinpointing the precise location of ureter dilatation with or without obstruction resulting from stone formation anywhere along the length of urinary tract and to isolate the obstruction from the dilation of the renal pelvis and calices. Since the obstruction or dilatation of ureter or kidney is bound to alter the parameters and patterns of ureteric jets, an imaging technique capable of generating dynamic image series of ureter jets will generate anatomical and functional information on the impediments to urine flow to bladder. In that context, while a recent clinical study on color Doppler reported that six-week silodosin therapy for male lower urinary tract symptoms (LUTS) changed the parameters and patterns of ureteric jets, an imaging technique capable of imaging the urinary tract of small animals is a prerequisite for an in-depth mechanistic investigation of drug's effect on ureteral jets.  While cystoscopy can assess the integrity of human ureter post-surgery, cystoscopy of mouse ureter is not yet feasible and the depiction of undilated ureter on unenhanced T2 weighted MR urography can be challenging. Accordingly, we developed a clinically viable technique of T1 weighted dynamic contrast enhanced (DCE) MRI for anatomical and functional imaging of lower and upper urinary tract in mouse model to advance the surgical and pharmacological interventions in urology.

Three month old female C57BL6 mice (n=3) were anesthetized via a nose cone with 1-2% isoflurane and O2, they were then positioned on an animal bed with the abdomen secured to reduce motion artifacts, and placed in the scanner. MRI was performed on a 7T/30-cm AVIII spectrometer (Bruker Biospin, Billerica, MA) using an 86 mm quadrature RF volume coil with a 4-channel receiver array. A T2-weighted rapid acquisition with resolution enhancement (RARE) sequence was used for anatomical scans in either an axial, coronal or sagittal orientation, with the following parameters: repetition time (TR)/echo time (TE) = 3000/40 ms, field of view (FOV) of 40 mm2, acquisition matrix = 256 × 256, 15 slices with a slice thickness of 1 mm, 2 averages, and a RARE factor = 8. For quantitative Dynamic Contrast Enhanced (DCE) MRI, first a T1 map was determined with a variable TR sequence using the following parameters : TR = 400, 842, 1,410, 2,208, 3,554 and 10,000 ms, echo time (TE) = 7 ms, 5 contiguous 0.8 mm slices, in the same orientation as the T2-weighted scan, RARE factor = 2, 2 averages, 20 mm2 FOV and a matrix size of 128 × 128. DCE-MRI was then performed with a series of either 100 or 200 dynamic RARE images with a temporal resolution of either 6.5 or 12.8 sec per frame with a TR/TE = 200/5 msec and the same geometry as the T1 map above. After approximately 10 pre-contrast frames, a bolus (10 sec duration) of Gadobutrol  0.1 mmol/kg was manually injected via a tail-vein catheter placed during animal preparation for DCE- MRI.

We evaluated the anatomy and function of mouse ureter by T1 weighted DCE-MRI using spin echo as gradient echo can accentuate the intrinsic radiofrequency inhomogeneity of pelvic region (ref.3).  Given that mouse rapidly turnovers its entire blood volume of 70mL/kg in less than 7s and the temporal resolution of our approach can not go down below 6.5s, the dynamic contrast enhancement (DCE) of the mouse bladder wall coincided with the DCE of iliac artery supplying blood to bladder wall. The spatial and temporal resolution were adjusted across slices as renal pelvis and ureter were better depicted in coronal and sagittal slices compared to axial slice.  While DCE scans that lasted 21 min had longer interval of 12s,  DCE scans that lasted 10min had shorter interframe interval of 6.5s between 100 frames and the shorter temporal resolution 6.5s was fast enough to ensure an adequate sampling of the rapid signal variations at ureteropelvic junction (UPJ) and at ureterovesical junction (UVJ) during the excretory phase of DCE-MRI. Furthermore, since injected Gadobutrol can neither be metabolized in liver nor it can gain entry inside the cells, injected Gadobutrol exclusively resides in blood and in extra cellular fluid space of mouse body before glomerular filtration by kidney without any reabsorption or secretion by renal tubule as the primary mode of clearance. Therefore, urinary excretion of Gadobutrol generates dynamic image series of ureteral jets for judging the ureter peristalsis and the metrics of ureteral jets (flow rate, volume) in different planes of DCE-MRI to view the bilateral jets (Fig.1). While 5 slices with narrow FOV of T1 weighted dynamic image series can reveal the functional integrity of ureter, information on the structural integrity of ureter at UPJ and UVJ can be gleaned from different anatomical T2 weighted slices (n=15) of higher thickness acquired with broader FOV before and after DCE-MRI.

The small size of mouse makes real time visualization of ureteral jets challenging with available imaging modalities (ref.2). While efficient, the imaging of urinary tract obstruction by ultrasound and CT does not provide any reliable information of kidney function whereas the information generated by dynamic nuclear scintigraphy is marred by poor spatial resolution of kidney. In that context, superior soft tissue resolution of ureter along entire length of tract without useing ionizing radiation in DCE-MRI can be valuable for generating diagnostic information about kidney function in pediatric and in pregnant population. Here, we demonstrate that the visualization of bilateral ureteral jets in mice by high temporal and spatial resolution with DCE-MRI at 7T is comparable to 11.7T (ref.3). Since injected Gadobutrol is only excreted by kidney, multislice  DCE-MRI can serve as one-stop diagnostic technique for the location of upper urinary tract dilatation with or without the obstruction from ureteral stones as well as for exclusion of hydronephrosis. The slow flow rate of urine tainted with excreted Gadobutrol at UPJ can index the lower glomerular filtration rate (GFR) for evaluating the suspicion of kidney disease raised by low creatinine clearance and the normal, pulsatile arrival of urine tainted with excreted Gadobutrol at UVJ can non-invasively index the ureter peristalsis and the metrics of ureteral jets. Instead of injecting Fluorescein or ingesting Riboflavin (Vitamin B2) for imbuing fluorescence to urine in invasive, real time assessment of ureteral flow by cystoscopy, the injection of paramagnetic dye, Gadobutrol taints urine to visualize ureteral jets by DCE-MRI in non-invasive manner that is amenable for machine learning. While DCE-MRI is not recommended for patients with renal insufficiency, contrast-free T2 weighted MRI can generate structural imaging of upper and lower urinary tract for identifying ureteral kinks in high risk population undergoing pelvic surgery or reconstruction or those at risk of ureteral stones.

Instead of the renal excretion of fluorescent dyes or vitamins, we relied on renal excretion of paramagnetic dye to report the first reliable visualization of mouse bilateral ureteral jets at 7T in non-invasive, radiation-free manner that is amenable for machine learning. Dynamic image series of clinically viable, non-invasive DCE-MRI generates anatomical and functional evidence of ureteral patency at UVJ and at kidney for potential longitudinal non-cystoscopic, radiation-free assessment of ureteral integrity after surgery and reconstruction on the same animal. Thus, DCE-MRI could be a "one-stop shop" of urography together with functional kidney evaluation during ureteral obstruction and nephropathy.

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Continence 12S (2024) 101378
DOI: 10.1016/j.cont.2024.101378