Inhibition of PDE-4 isoenzyme attenuates frequency and overall contractility of agonist-evoked ureteral phasic contractions.

The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 µM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 µM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 µM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 µM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.

Numerical analysis of an obstacle motion in the human ureter using the dynamic mesh approach.

Peristalsis is a common motion in various biological systems, especially the upper urinary tract, where it plays a pivotal role in conveying urine from the kidneys to the bladder. Using computational fluid dynamics, this study aims to investigate the effect of various peristaltic parameters on the motion of an obstacle through a two-dimensional ureter. Methodologically, Incompressible Navier-Stokes equations were utilized as the fluid domain's governing equations, and the Dynamic Mesh method (DM) was employed to simulate the peristaltic and obstacle motion. The peristaltic motion was modeled by a sinusoidal contraction wave propagating alongside the ureter at the physiological speed, and the motion of the obstruction through the ureter, which is caused by the fluid forces applied on its surface, was explored using the equation of Newton's second law. Various test cases of different shapes and sizes were supposed as kidney stones to understand the influence of the peristalsis properties on the stone removal process. The results show that the motion of the kidney stone is highly influenced by the gradient pressure force applied to its surface in the fluid domain. Moreover, investigating the effects of the peristaltic physical properties on the obstacle's motion indicates that the stone's motion is dependent on these parameters. Furthermore, this analysis provides insight into the peristaltic motion effects, assisting physicians in developing new medicines to facilitate the kidney stone removal process based on its shape and size.

Peristalsis prevents ureteral dilation.

PURPOSE: The etiology of ureteral dilation in primary nonrefluxing, nonobstructing megaureters is still not well understood. Impaired ureteral peristalsis has been theorized as one of the contributing factors. However, ureteral peristalsis and its "normal" function is not well defined. In this study, using mathematical modeling techniques, we aim to better understand how ureteral peristalsis works. This is the first model to consider clinically observed, back-and-forth, cyclic wall longitudinal motion during peristalsis. We hypothesize that dysfunctional ureteral peristalsis, caused by insufficient peristaltic amplitudes (e.g., circular muscle dysfunction) and/or lack of ureteral wall longitudinal motion (e.g., longitudinal muscle dysfunction), promotes peristaltic reflux (i.e., retrograde flow of urine during an episode of peristalsis) and may result in urinary stasis, urine accumulation, and consequent dilation. METHODS: Based on lubrication theory in fluid mechanics, we developed a two-dimensional (planar) model of ureteral peristalsis. In doing so, we treated ureteral peristalsis as an infinite train of sinusoidal waves. We then analyzed antegrade and retrograde flows in the ureter under different bladder-kidney differential pressure and peristalsis conditions. RESULTS: There is a minimum peristaltic amplitude required to prevent peristaltic reflux. Ureteral wall longitudinal motion decreases this minimum required amplitude, increasing the nonrefluxing range of peristaltic amplitudes. As an example, for a normal bladder-kidney differential pressure of 5 cmH2 O, ureteral wall longitudinal motion increases nonrefluxing range of peristaltic amplitude by 65%. Additionally, ureteral wall longitudinal motion decreases refluxing volumetric flow rates. For a similar normal bladder pressure example of 5 cmH2 O, refluxing volumetric flow rate decreases by a factor of 18. Finally, elevated bladder pressure, not only increases the required peristaltic amplitude for reflux prevention but it increases maximum refluxing volumetric flow rates. For the case without wall longitudinal motion, as bladder-kidney differential pressure increases from 5 to 40 cmH2 O, minimum required peristaltic amplitude to prevent reflux increases by 40% while the maximum refluxing volumetric flow rate increases by approximately 100%. CONCLUSION: The results presented in this study show how abnormal ureteral peristalsis, caused by the absence of wall longitudinal motion and/or lack of sufficient peristaltic amplitudes, facilitates peristaltic reflux and retrograde flow. We theorize that this retrograde flow can lead to urinary stasis and urine accumulation in the ureters, resulting in ureteral dilation seen on imaging studies and elevated infection risk. Our results also show how chronically elevated bladder pressures are more susceptible to such refluxing conditions that could lead to ureteral dilation.

Propagation of Pacemaker Activity and Peristaltic Contractions in the Mouse Renal Pelvis Rely on Ca2+-activated Cl- Channels and T-Type Ca2+ Channels.

The process of urine removal from the kidney occurs via the renal pelvis (RP). The RP demarcates the beginning of the upper urinary tract and is endowed with smooth muscle cells. Along the RP, organized contraction of smooth muscle cells generates the force required to move urine boluses toward the ureters and bladder. This process is mediated by specialized pacemaker cells that are highly expressed in the proximal RP that generate spontaneous rhythmic electrical activity to drive smooth muscle depolarization. The mechanisms by which peristaltic contractions propagate from the proximal to distal RP are not fully understood. In this study, we utilized a transgenic mouse that expresses the genetically encoded Ca2+ indicator, GCaMP3, under a myosin heavy chain promotor to visualize spreading peristaltic contractions in high spatial detail. Using this approach, we discovered variable effects of L-type Ca2+ channel antagonists on contraction parameters. Inhibition of T-type Ca2+ channels reduced the frequency and propagation distance of contractions. Similarly, antagonizing Ca2+-activated Cl- channels or altering the transmembrane Cl- gradient decreased contractile frequency and significantly inhibited peristaltic propagation. These data suggest that voltage-gated Ca2+ channels are important determinants of contraction initiation and maintain the fidelity of peristalsis as the spreading contraction moves further toward the ureter. Recruitment of Ca2+-activated Cl- channels, likely Anoctamin-1, and T-type Ca2+ channels are required for efficiently conducting the depolarizing current throughout the length of the RP. These mechanisms are necessary for the efficient removal of urine from the kidney.

Quasi-linear viscoelastic behavior of fresh porcine ureter.

PURPOSE: To evaluate the viscoelastic properties of the fresh porcine ureter. Prove the QLV theory can sufficiently model the stress relaxation function of porcine ureters, and determine the QLV model constants which may provide insight into the synthesis of ureteral scaffolds with biomimetic viscoelastic properties in tissue engineering. METHODS: Hysteresis tests were applied to study the differences in dissipated energy ratio for each different strain group. In stress relaxation tests, samples were sub-grouped and quickly ramping up to 5%, 20%, and 30% strain in each group and gradually relaxed to a corresponding level. Bringing together the quasi-linear viscoelasticity (QLV) theory and stress relaxation function to determine the eight constants of the ureteral tissue, and fitting the raw data with the model via MATLAB. RESULTS: The hysteresis response measurement results revealed that the porcine ureter was a highly dissipative material and there were differences between toe and linear region in stress-stain curve. The stress relaxation results revealed ureters responded with time-dependent decay of stress. The eight constants of the ureteral QLV model were determined for three different strain groups, and we proved that the QLV model can sufficiently adapt the experimental data of the ureter stress relaxation. CONCLUSION: This study investigated the time-dependent properties of the porcine ureter, and demonstrated the QLV theory could be used to evaluate the viscoelastic properties of the porcine ureteral tissue.

Neurophysiological aspects of electrical pulse stimulation in patients with urolithiasis.

Stimulation of the peristaltic activity of the ureter is a pathogenetically substantiated component of the lithokinetic effect. AIM: The aim of the work was to study the effects of electrical impulse stimulation on ureteral motility in patients with urolithiasis. MATERIALS AND METHODS: 47 patients with urolithiasis, aged 27-59 years, with unilateral ureteral stones, up to 5 mm in size, were studied. The patients underwent translumbar electrical impulse stimulation according to the original method. The results were assessed by the change in the frequency of ureteral emissions and the duration of the interval between two consecutive ureteral emissions. RESULTS: As a result of the method used, there is an increase in the average frequency of ureteral ejections from 1.38±0.49 to 2.20±0.84 minutes (p<0.05), a decrease in the average duration of the interval between two consecutive ureteral ejections from 44.48 ±7 .89 to 27.96±3.89 seconds (p<0.05). The impact was well tolerated by patients. There were no changes in hemodynamic parameters. CONCLUSIONS: Transdermal exposure to single electric stimuli of a rectangular shape has significant effect in patients with urolithiasis as electric pulse stimulation helps to increase the peristaltic activity of the ureter by initiating additional peristaltic waves. To achieve this effect, it is advisable to apply range of 15-30 mA at a time moment corresponding to the last third of the interval between ureteral emissions, when applying stimulating electrodes in the lumbar region, in the area of the projection of the renal pelvis and the proximal ureter.

TRPM3 channel activation inhibits contraction of the isolated human ureter via CGRP released from sensory nerves.

AIMS: Sensory nerve activation modulates ureteral contractility by releasing neuropeptides including CGRP and neurokinin A (NKA). TRPM3 is a recently discovered thermosensitive channel expressed in nociceptive sensory neurons, and plays a key role in heat nociception and chronic pain. The aim of this study is to examine the role of TRPM3 activation in human ureter motility. MAIN METHOD: Human proximal ureters were obtained from fourteen patients undergoing nephrectomy. Spontaneous or NKA-evoked contractions of longitudinal ureter strips were recorded in an organ bath. Ureteral TRPM3 expression was examined by immunofluorescence. KEY FINDINGS: Spontaneous contractions were observed in 60% of examined strips. TRPM3 activation using pregnenolone sulphate (PS) or CIM0216 (specific TRPM3 agonists) dose-dependently reduced the frequency of spontaneous and NKA-evoked contractions, with IC50s of 241.7 µM and 4.4 µM, respectively. The inhibitory actions of TRPM3 agonists were mimicked by CGRP (10 to 100 nM) or a cAMP analogue (8-Br-cAMP; 1 mM). The inhibitory actions of TRPM3 agonists (300 µM PS or 30 µM CIM0216) were blocked by pretreatment with primidone (TRPM3 antagonist; 30 µM), tetrodotoxin (sodium channel blocker; 1 µM), olcegepant (CGRP receptor antagonist; 10 µM), or H89 (non-specific PKA inhibitor; 30 µM). TRPM3 was co-expressed with CGRP in nerves in the sub-urothelial and intermuscular regions of the ureter. SIGNIFICANCE: TRPM3 channels expressed on sensory terminals of the human ureter involve in inhibitory sensory neurotransmission and modulate ureter motility via the CGRP-cAMP-PKA signal pathway. Targeting TRPM3 may be a pharmacological strategy for promoting the ureter stone passage.

There are no three physiological narrowings in the upper urinary tract: a new concept of the retroperitoneal anatomy around the ureter.

The widely held dogma of three physiological narrowings in the upper urinary tract has proven incorrect by recent several studies using computed tomography images. There are only two common obstruction sites: the upper ureter and the ureterovesical junction. The second narrowing, where the ureter crosses the iliac vessels, cannot be regarded anymore as a common obstruction site. The mechanism by which stones lodge in the upper ureter is explained anatomically by the change in ureteral mobility and compliance at the level where the ureter exits the perirenal space. This level can be identified radiologically as the point where the ureter crosses under the ipsilateral gonadal veins, termed the "crossing point". Kinking of the upper ureter is another manifestation of this anatomical phenomenon, visible in radiological images. It is caused by loosening of the ureter at or above the crossing point (within the perirenal space), corresponding with renal descent such as during the inspiratory phase. This new anatomical discovery in the retroperitoneum will not only bring about a paradigm shift in terms of the physiological narrowings in the upper urinary tract, but may also lead to the development of new surgical concepts and approaches in the area.

The transient receptor potential A1 ion channel (TRPA1) modifies in vivo autonomous ureter peristalsis in rats.

AIMS: The current study aimed to explore the expression of transient receptor potential A1 ion channels (TRPA1) in the rat ureter and to assess if TRPA1-active compounds modulate ureter function. METHODS: The expression of TRPA1 in rat ureter tissue was studied by immunofluorescence. The TRPA1 distribution was compared to calcitonin gene-related peptide (CGRP), α-actin (SMA1), anoctamin-1 (ANO1), and c-kit. For in vivo analyses, a catheter was implanted in the right ureter of 50 rats. Ureter peristalsis and pressures were continuously recorded by a data acquisition set-up during intraluminal infusion of saline (baseline), saline plus protamine sulfate (PS; to disrupt the urothelium), saline plus PS with hydrogen sulfide (NaHS) or cinnamaldehyde (CA). Comparisons were made between rats treated systemically with vehicle or a TRPA1-antagonist (HC030031). RESULTS: TRPA1-immunoreactive nerves co-expressed CGRP and were mainly located in the suburothelial region of the ureter. Immunoreactivity for TRPA1 was also encountered in c-kit-positive but ANO1-negative cells of the ureter suburothelium and wall. In vivo, HC030031-treated rats had elevated baseline peristaltic frequency (p < 0.05) and higher intraluminal pressures (p < 0.01). PS increased the frequency of ureter peristalsis versus baseline in vehicle-treated rats (p < 0.001) but not in HC030031-treated rats. CA (p < 0.001) and NaHS (p < 0.001) decreased ureter peristalsis. This was counteracted by HC030031 (p < 0.05 and p < 0.01). CONCLUSIONS: In rats, TRPA1 is expressed on cellular structures considered of importance for peristaltic and mechanoafferent functions of the ureter. Functional data indicate that TRPA1-mediated signals regulate ureter peristalsis. This effect was pronounced after mucosal disruption and suggests a role for TRPA1 in ureter pathologies involving urothelial damage.

An abundant quiescent stem cell population in Drosophila Malpighian tubules protects principal cells from kidney stones.

Adult Drosophila Malpighian tubules have low rates of cell turnover but are vulnerable to damage caused by stones, like their mammalian counterparts, kidneys. We show that Drosophilarenal stem cells (RSCs) in the ureter and lower tubules comprise a unique, unipotent regenerative compartment. RSCs respond only to loss of nearby principal cells (PCs), cells critical for maintaining ionic balance. Large polyploid PCs are outnumbered by RSCs, which replace each lost cell with multiple PCs of lower ploidy. Notably, RSCs do not replenish principal cells or stellate cells in the upper tubules. RSCs generate daughters by asymmetric Notch signaling, yet RSCs remain quiescent (cell cycle-arrested) without damage. Nevertheless, the capacity for RSC-mediated repair extends the lifespan of flies carrying kidney stones. We propose that abundant, RSC-like stem cells exist in other tissues with low rates of turnover where they may have been mistaken for differentiated tissue cells.

Excitation-Contraction Coupling in Ureteric Smooth Muscle: Mechanisms Driving Ureteric Peristalsis.

The ureter acts as a functional syncytium and is controlled by a propagating plateau-type action potential (AP) which gives rise to a wave of contraction (ureteral peristalsis) via a process called excitation-contraction (E-C)coupling. The second messenger Ca2+ activates Ca2+/calmodulin-dependent myosin light chain kinase-dependent phosphorylation of 20-kDa regulatory light chains of myosin which leads to ureteric contraction. Ca2+ entry from the extracellular space via voltage-gated L-type Ca2+ channels (VGCCs) provides the major source of activator Ca2+, responsible for generation of both the AP and a Ca2+ transient that appears as an intercellular Ca2+ wave. The AP, inward Ca2+ current, Ca2+ transient and twitch contraction are all fully blocked by the selective L-type Ca2+ channel blocker nifedipine. Ca2+ entry via VGCCs, coupled to activation of Ca2+-sensitive K+ (KCa) or Cl- (ClCa) channels, acts as a negative or positive feedback mechanism, respectively, to control excitability and the amplitude and duration of the plateau component of the AP, Ca2+ transient and twitch contraction. The ureter, isolated from the pelvis, is not spontaneously active. However, spontaneous activity can be initiated in the proximal and distal ureter by a variety of biological effectors such as neurotransmitters, paracrine, endocrine and inflammatory factors. Applied agonists depolarise ureteric smooth muscles cells to threshold of AP activation, initiating propagating intercellular AP-mediated Ca2+ waves to produce antegrade and/or retrograde ureteric peristalsis. Several mechanisms have been proposed to describe agonist-induced depolarization of ureteric smooth muscle, which include suppression of K+ channels, stimulation of ClCa current and activation of non-selective cation receptor/store operated channels.

In vitro study of age-related changes in human ureteral failure properties according to region, direction, and layer.

Knowledge of the capacity of the ureteral wall to withstand urodynamic or external stresses is essential to understand ureteral injury and rupture that mostly occur following trauma, but may also be secondary to obstructive uropathy. It has clinical significance as well in the prevention of iatrogenic injury, for example, during ureteroscopy, but no information is available with regard to the age-related failure properties and regional differences have not been systematically described. Uniaxial tensile testing was performed on 166 ureteral rings and strips from 21 humans free of overt urologic disease; histological evaluation was performed. The degree of layer participation to the intact wall failure stress (=tissue strength), peak elastic modulus (=stiffness), and failure stretch (=extensibility) was assessed by examining layer-specific ruptures in the stress-stretch data. Failure stress at and peak elastic modulus before the first (muscle/adventitial) rupture correlated inversely less with age ( p < 0.05 in few regions/directions) than failure stress at the second (mucosal) rupture ( p < 0.05 in the middle and lower ureter), consistent with the decreased mucosal thickness in ≥50-year-old subjects. Failure stretch at both ruptures did not correlate with age ( p > 0.05 in most regions/directions), paralleling elastin content. Correlations with age were more significant in females than males. Failure stress at the second rupture point was higher ( p < 0.05) distally in <50-year-old but not in ≥50-year-old subjects, justified by the increased collagen distally in the former. Directional differences in failure stretches ( p < 0.05 at all ages/regions/genders) were justified by preferentially axial collagen reinforcement. The presented results may establish the foundation for computational models of iatrogenic/accidental ureteral trauma.

Ureter tissue engineering with vessel extracellular matrix and differentiated urine-derived stem cells.

OBJECTIVE: To assess the possibility of ureter tissue engineering using vessel extracellular matrix (VECM) and differentiated urine-derived stem cells (USCs) in a rabbit model. METHODS: VECM was prepared by a modified technique. USCs were isolated from human urine samples and cultured with an induction medium for the differentiation of the cells into urothelium and smooth muscle phenotypes. For contractile phenotype conversion, the induced smooth muscle cells were transfected with the miR-199a-5p plasmid. The differentiated cells were seeded onto VECM and cultured under dynamic conditions in vitro for 2 weeks. The graft was tubularized and wrapped by two layers of the omentum of a rabbit for vascularization. Then, the maturated graft was used for ureter reconstruction in vivo. RESULTS: VECM has microporous structures that allow cell infiltration and exhibit adequate biocompatibility with seeding cells. USCs were isolated and identified by flow cytometry. After induction, the urothelium phenotype gene was confirmed at mRNA and protein levels. With the combined induction by TGF-ß1 and miR-199a-5p, the differentiated cells can express the smooth muscle phenotype gene and convert to the contractile phenotype. After seeding cells onto VECM, the induced urothelium cells formed a single epithelial layer, and the induced smooth muscle cells formed a few cell layers during dynamic culture. After 3 weeks of omental maturation, tubular graft was vascularized. At 2 months post ureter reconstruction, histological evaluation showed a clearly layered structure of ureter with multilayered urothelium over the organized smooth muscle tissue. CONCLUSION: By seeding differentiated USCs onto VECM, a tissue-engineered graft could form multilayered urothelium and organized smooth muscle tissue after ureteral reconstruction in vivo. STATEMENT OF SIGNIFICANCE: Cell-based tissue engineering offers an alternative technique for urinary tract reconstruction. In this work, we describe a novel strategy for ureter tissue engineering. We modified the techniques of vessel extracellular matrix (VECM) preparation and used a dynamic culture system for seeding cells onto VECM. We found that VECM had the trait of containing VEGF and exhibited blood vessel formation potential. Urine-derived stem cells (USCs) could be differentiated into urothelial cells and functional contractile phenotype smooth muscle cells in vitro. By seeding differentiated USCs onto VECM, a tissue-engineered graft could form multilayered urothelium and organized smooth muscle tissue after ureteral reconstruction in vivo. This strategy might be applied in clinical research for the treatment of long-segment ureteral defect.

Oral Riboflavin to Assess Ureteral Patency During Cystoscopy: A Randomized Clinical Trial.

OBJECTIVE: To evaluate whether oral riboflavin is more effective than placebo as a marker of ureteric patency at cystoscopy. METHODS: Patients scheduled for gynecologic surgery where cystoscopy was a planned component of the procedure were randomized to receive riboflavin 400 mg or placebo orally the night before surgery. During cystoscopy, the operating surgeon visualized ureteric jets and video recorded the cystoscopy portion of the procedure. The primary outcome was to determine whether orally administered riboflavin produced stronger yellow color of urine seen on cystoscopy than placebo on a 3-point scale. Secondary outcomes were to assess whether riboflavin administration improved ease of identifying ureteric jets (5-point scale) and whether a greater proportion of patients had both ureteric jets visualized with riboflavin compared with placebo. A sample size of 33 per group was planned. RESULTS: From June 28, 2017, to February 19, 2018, 72 women were screened and 66 were randomized, with 33 patients in each study group. The groups were similar in age, weight, body mass index, and ethnicity. The patients in the riboflavin group had significant increase of yellow-colored urine as rated by the operating surgeon, with a median of 2 compared with 1 on a 3-point scale (P<.001). The ureteral jets were more easily visualized in the riboflavin group as rated by the operating surgeon, with a median of 5 compared with 4 on a 5-point scale (P<.013). Bilateral ureteral patency was confirmed in 30 of 33 women (91%) in the riboflavin group and in 28 of 33 women (85%) in the placebo group (P=.71). CONCLUSIONS: The administration of riboflavin before gynecologic surgery improves the ease of visualizing the ureteric jets by inducing yellow coloration of the urine. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry, 12616001367437.

Cardiac electrophysiology catheters for electrophysiological assessments of the lower urinary tract-A proof of concept ex vivo study in viable ureters.

AIMS: To explore the feasibility of minimally invasive catheter-based electrophysiology studies in the urinary tract. This is a well-known method used in cardiology to investigate and treat arrhythmias. METHODS: We developed an experimental platform which allows electrophysiological recordings with cardiac catheters and conventional needle electrodes in ex vivo pig ureters. The action potential was triggered by a stimulating electrode. We considered 13 porcine ureters (freshly collected and harvested in organ bath), 7 of which were used to optimize the setup and define the stimulation parameters; we performed the recordings in the remaining six ureters. The electrical propagation of the generated action potential was tracked with multiple sensing electrodes, from which propagation directions, velocities, refractory periods, and pacing thresholds were extracted. RESULTS: We recorded propagating electrical activity in four ureters using needle electrodes and in two ureters using cardiac catheters. Propagation velocities for forward direction (from kidney to bladder) derived by the two methods were similar (15.1 ± 2.6 mm/s for cardiac catheters, 15.6 ± 2.3 mm/s for needle recordings). Pacing thresholds, activation patters, and refractory times were provided for the ureteric smooth muscle. Retrograde propagations and corresponding velocities were also observed and measured. CONCLUSIONS: This study is a proof-of-concept showing that electrical activity can be measured "from the inside" of urinary cavities using catheters and that obtained results are comparable with the more invasive needle recordings. Catheter-based electrophysiology may allow, in the clinical setting, for: i) a more differentiated understanding of urological disorders such as overactive bladder and ii) new therapeutic approaches (e.g., targeted tissue ablation).

A two way fully coupled fluid structure simulation of human ureter peristalsis.

Numerical simulations of ureter peristalsis have been carried out in the past to understand both the flow field and ureter wall mechanics. The main objective of the current investigations is to have a better understanding of the urine transport due to the peristalsis in the ureter, thus making the information helpful for a better treatment and diagnosis of ureteral complications like urine reflux. In the current study, a numerical simulation is performed using a finite-element-based solver with a two-way fully coupled fluid structure interaction approach between the ureter wall and urine. For the first time, the ureter wall is modeled as an anisotropic hyper-elastic material based on experiments performed in previous literature on the human ureter. Peristalsis in the ureter is modeled as a series of isolated boluses. By observing the flow field it is clear that the peristalsis mechanism has a natural tendency to create a backflow as the isolated bolus moves forward. As a result, the urine can flow back from the bladder to the ureter at the ureterovesical (ureter-bladder) junctions, if the one-way valve starts to malfunction.

Transcriptome-driven integrative exploration of functional state of ureter tissue affected by CAKUT.

AIMS: (1) to identify the most dysregulated genes in ureter tissue affected by congenital anomalies of the kidney and urinary tract (CAKUT) and to extract the biological meaning of these markers; (2) to describe the key molecular networks in CAKUT and to provide expression validation of the genes selected from these networks. MAIN METHODS: Transcriptome data was obtained from ureter samples of CAKUT patients and controls by Illumina iScan microarray. Identification of differentially expressed genes was coupled with subsequent bioinformatics analyses. Expression of candidate genes was validated by qRT-PCR. KEY FINDINGS: Analysis of the transcriptome led to the identification of 78 commonly dysregulated genes in CAKUT tissue compared to controls. Integrative bioinformatic analyses of differentially expressed genes identified 7 major networks. The targets for qRT-PCR validation were selected as members of the major molecular networks in CAKUT, which had both, the significant high fold change and biological relevance for CAKUT. By qRT-PCR the substantial increase of LCN2, PROM1, SOSTDC1, and decrease of INA, RASD1 and TAC3 mRNA levels was confirmed. SIGNIFICANCE: Since CAKUT is a leading cause of end-stage renal disease in children, the search for molecular targets for postnatal therapy is of particular interest. Data described in this study represents the gene expression profile and significant molecular networks specific to human ureter affected by CAKUT. The discovery of impaired molecular factors and processes is the step towards the uncovering of the key mechanisms that reflect CAKUT postnatally and could lead to the affected tissue deterioration and end organ damage.

A three-dimensional (3D) two-way coupled fluid-structure interaction (FSI) study of peristaltic flow in obstructed ureters.

Obstruction in the ureter flow path is one of the most common problems in urinary-related diseases. As the ureter transports the urine using the expansion bolus created by the peristaltic pulses, an obstruction in its path can cause unwanted backflow and can also result in damage to the wall. But in order to understand this further, and specifically to quantify and parametrize the effect of the obstruction in the ureter, a detailed study investigating various level of obstructions in peristaltic ureter flow is necessary. In the current study, full 3D numerical simulations of peristalsis in an obstructed ureter are carried out using a finite element solver along with a two-way coupling between the fluid and structural domain with the arbitrary Eulerian-Lagrangian method. Analysis of the results shows that the larger the obstruction, the higher the wall shear stress and pressure gradient in the fluid. In addition, the amount of backflow increases with increase in the obstruction.

A fluid-structure interaction (FSI)-based numerical investigation of peristalsis in an obstructed human ureter.

Urine moves from the kidney to the bladder through the ureter. A series of compression waves facilitates this transport. Due to the highly concentrated mineral deposits in urine, stones are formed in the kidney and travel down through the urinary tract. While passing, a larger stone can get stuck and cause severe damage to ureter wall. Also, stones in the ureter obstructing the urine flow can cause pain and backflow of urine which in turn might require surgical intervention. The current study develops a 2D axisymmetric numerical model to gain an understanding of the ureter obstruction and its effects on the flow, which are critical in assessing the different treatment options. Transient computational analysis involving a two-way fully coupled fluid-structure interaction with the arbitrary Lagrangian-Eulerian method between the ureteral wall and urine flow is conducted with an obstruction in the ureter. The ureter wall is modeled as an anisotropic hyperelastic material, data of which, is based on biaxial tests on human ureter from previous literature, while the incompressible Navier-Stokes equations are solved to calculate urine flow. A finite element-based monolithic solver is used for the simulations here. The obstruction is placed in the fluid domain as a circular stone at the proximal part of the ureter. One of the objectives of this study is to quantify the effect of the ureteral obstruction. A sharp jump in pressure gradient and wall shear stress, as well as retrograde urine flow, is observed as a result of the obstruction.

Contractile responses in intact and mucosa-denuded human ureter-a comparison with urinary bladder detrusor preparations.

Human proximal and distal ureter tissues were studied to clarify whether the presence of mucosa affects contractile responses. In histological studies, human ureter was compared with urinary bladder (detrusor). Contractions in response to high KCl solution, phenylephrine, and carbachol were measured in intact and mucosa-denuded strips of human ureter. Tissue sections of human bladder and ureter were used for histological staining. Thirty-four percent of the ureter strips contracted spontaneously with highly variable patterns, and this was affected neither by mucosa nor by proximal or distal tissue origin. Upon stimulation with 40 mM KCl, ureter strips exhibited strong phasic and weak tonic contractions. In intact strips, normalized tonic force was lower than in denuded strips, but no consistent effect of mucosa was observed with phasic contractions. Absolute force values of phasic contractions were weaker in proximal than distal ureter strips, but similar when normalized to tissue wet weight. Stimulation with 80 mM KCl enhanced tonic contraction fourfold; phasic contractions occurred rarely. Phenylephrine produced no statistically significant stronger tonic contraction in distal compared with proximal ureter strips; nevertheless, in some strips, pre-existing spontaneous contractions increased. Carbachol did not influence ureter contractions. In the bladder, a suburothelial cell layer stained positive with α-smooth muscle actin (α-SMA)-specific antibodies could be further differentiated with vimentin- and desmin-specific antibodies. α-SMA positive cells were absent in suburothelial ureter tissue. Like in detrusor, the mucosa inhibits KCl-stimulated tonic ureter contractions. The mucosa of detrusor and ureter tissue exhibits distinct staining patterns for α-SMA, vimentin, and desmin. This suggests a different distribution of smooth muscle cells, fibroblasts, and myofibroblasts, which could be a target for pharmacological therapy of pathologic contractile processes.