Numerical simulation of the urine flow in a stented ureter

When a stent is implanted in a blocked ureter, the urine passing from the kidney to the bladder must traverse a very complicated flow path. That path consists of two parallel passages, one of which is the bore of the stent and the other is the annular space between the external surface of the stent and the inner wall of the ureter. The flow path is further complicated by the presence of numerous pass-through holes that are deployed along the length of the stent. These holes allow urine to pass between the annulus and the bore. Further complexity in the pattern of the urine flow occurs because the coiled "pig tails," which hold the stent in place, contain multiple ports for fluid ingress and egress. The fluid flow in a stented ureter has been quantitatively analyzed here for the first time using numerical simulation. The numerical solutions obtained here fully reveal the details of the urine flow throughout the entire stented ureter. It was found that in the absence of blockages, most of the pass-through holes are inactive. Furthermore, only the port in each coiled pig tail that is nearest the stent proper is actively involved in the urine flow. Only in the presence of blockages, which may occur due to encrustation or biofouling, are the numerous pass-through holes activated. The numerical simulations are able to track the urine flow through the pass-through holes as well as adjacent to the blockages. The simulations are also able to provide highly accurate results for the kidney-to-bladder urine flow rate. The simulation method presented here constitutes a powerful new tool for rational design of ureteral stents in the future.     

Correction of experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon.

Vesicoureteric reflux was produced in eight piglets by opening their bladders and slitting the anterior intravesical wall of the ureter. Cystography confirmed the presence of bilateral reflux in six piglets and unilateral reflux in two. Six to eight weeks later the bladder was again opened and Teflon paste injected in the space behind the intravesical ureter, thereby creating a support for the submucosal ureter. Cystography four to six weeks after injection of Teflon paste showed absence of reflux in all animals. Intravenous pyelography showed obstruction at the vesicoureteric junction in only one of the 14 treated ureters and this was later confirmed at necropsy. Animals were followed up from one to six months and then were killed. Gross examination of the vesicoureteric region showed a well circumscribed subureteric Teflon mass of firm consistency, retaining its shape and position at the site of the injection. Histological examination showed encapsulation of the implant by a thin layer of fibrous tissue and a foreign body granulomatous reaction with histiocytes and giant cells within the implant. Hence it is technically feasible to correct experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon paste--a relatively inert material. It may now be possible to treat vesicoureteric reflux in man by endoscopic injection of Teflon behind the intravesical ureter.     

Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder?

Urothelial umbrella cells are characterized by apical, rigid membrane plaques, which contain four major uroplakin proteins (UP Ia, Ib, II and III) forming UPIa/UPII and UPIb/UPIII pairs. These integral membrane proteins are thought to play an important role in maintaining the physical integrity and the permeability barrier function of the urothelium. We asked whether the four uroplakins always coexpress in the entire human lower urinary tract. We stained immunohistochemically (ABC-peroxidase method) paraffin sections of normal human ureter (n = 18) and urinary bladder (n = 10) using rabbit antibodies against UPIa, UPIb, UPII and UPIII; a recently raised mouse monoclonal antibody (MAb), AU1, and two new MAbs, AU2 and AU3, all against UPIII; and mouse MAbs against umbrella cell-associated cytokeratins CK18 and CK20. Immunoblotting showed that AU1, AU2 and AU3 antibodies all recognized the N-terminal extracellular domain of bovine UPIII. By immunohistochemistry, we found that in 15/18 cases of human ureter, but in only 2/10 cases of bladder, groups of normal-looking, CK18-positive umbrella cells lacked both UPIII and UPIb immunostaining. The UPIb/UPIII-negative cells showed either normal or reduced amounts of UPIa and UPII staining. These data were confirmed by double immunofluorescence microscopy. The distribution of the UPIb/UPIII-negative umbrella cells was not correlated with localized urothelial proliferation (Ki-67 staining) or with the distribution pattern of CK20. Similar heterogeneities were observed in bovine but not in mouse ureter. We provide the first evidence that urothelial umbrella cells are heterogeneous as some normal-looking umbrella cells can possess only one, instead of two, uroplakin pairs. This heterogeneity seems more prominent in the urothelium of human ureter than that of bladder. This finding may indicate that ureter urothelium is intrinsically different from bladder urothelium. Alternatively, a single lineage of urothelium may exhibit different phenotypes resulting from extrinsic modulations due to distinct mesenchymal influence and different degrees of pressure and stretch in bladder versus ureter. Additional studies are needed to distinguish these two possibilities and to elucidate the physiological and pathological significance of the observed urothelial and uroplakin heterogeneity.     

大鼠肾移植慢性排斥反应模型的建立

目的建立一种稳定的大鼠原位肾移植慢性排斥反应模型。方法供体为近交系F344大鼠,受体为Lewis大鼠,供肾采用左肾,在体修整,原位灌注。肾静脉用硬膜外导管做为临时内支架管端-端、六针法吻合,腹主动脉端-侧连续缝合,输尿管带膀胱瓣与膀胱吻合。受体术前3 d开始环孢素A灌胃至术后30 d（5 mg/kg·d）,以预防急性排斥反应。结果手术时间120～180 min;手术成功率90.9%（40P44）;受体均存活60 d。并发症有吻合口出血、静脉血栓形成、急性排斥反应等。结论供肾原位灌注,在体修整是简单可靠的方法。静脉內支架管端端吻合,腹主动脉端侧吻合能够达到稳定的成功率,值得推广。熟练的外科操作技能和血管吻合技术是手术成功的关键。     

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

Abstract

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.     

Computer assisted laparoscopic pneumovesical ureter reimplantation a.m. Cohen: initial experience in a pig model

To assess the feasibility of a new variant of laparoscopic Cohen cross-trigonal ureter reimplantation in vesico-ureteral reflux (VUR) using telesurgical equipment. VUR was induced in 8 female pigs by transurethral unroofing of the ureteric orifices. Three months later the reflux was verified by a cystography. A cross-trigonal ureter reimplantation a.m. Cohen was performed by laparoscopic access to the bladder using the da Vinci telesurgical system. The 12 mm camera port was placed below the umbilicus, two 8 mm working ports for the robotic system were placed lateral to the rectus muscles and an additional port for assistance between camera and right working port. The outcome was assessed 3 months later by a new cystography. The operative time for a single reimplantation varied from 45 to 90 minutes. In all pigs the reflux disappeared after the procedure, which was complicated by a postoperative port hernia in two animals. Laparoscopic transvesical ureter reimplantation using telesurgical equipment is a feasible method in the few cases this procedure is indicated. The advantage of the robotic equipment is the better access to submucosal tunneling of the ureter and the intravesical suturing of the anastomosis indicated by shorter operative time and success rates similar to the open procedure.     

Treatment of vesicoureteric reflux by endoscopic injection of Teflon.

Thirteen girls with grade III-V vesicoureteric reflux were treated by endoscopic injection of Teflon paste behind the intravesical ureter. Fourteen of the 18 treated ureters showed complete absence of reflux after one injection of Teflon. Three ureters required a second injection of Teflon for successful treatment of the reflux. One ureter with grade IV reflux was converted to grade II reflux. Properly carried out, this procedure corrects reflux. It takes less than 15 minutes, may be done as a day procedure, and avoids open surgery. There have been no complications.     

Differential gene expression in the developing mouse ureter

In many instances, kidney dysgenesis results as a secondary consequence to defects in the development of the ureter. Through the use of mouse genetics a number of genes associated with such malformations have been identified, however, the cause of many other abnormalities remain unknown. In order to identify novel genes involved in ureter development we compared gene expression in embryonic day (E) 12.5, E15.5 and postnatal day (P) 75 ureters using the Compugen mouse long oligo microarrays. A total of 248 genes were dynamically upregulated and 208 downregulated between E12.5 and P75. At E12.5, when the mouse ureter is comprised of a simple cuboidal epithelium surrounded by ureteric mesenchyme, genes previously reported to be expressed in the ureteric mesenchyme, foxC1 and foxC2 were upregulated. By E15.5 the epithelial layer develops into urothelium, impermeable to urine, and smooth muscle develops for the peristaltic movement of urine towards the bladder. The development of these two cell types coincided with the upregulation of UPIIIa, RAB27b and PPARgamma reported to be expressed in the urothelium, and several muscle genes, Acta1, Tnnt2, Myocd, and Tpm2. In situ hybridization identified several novel genes with spatial expression within the smooth muscle, Acta1; ureteric mesenchyme and smooth muscle, Thbs2 and Col5a2; and urothelium, Kcnj8 and Adh1. This study marks the first known report defining global gene expression of the developing mouse ureter and will provide insight into the molecular mechanisms underlying kidney and lower urinary tract malformations.     

A mathematical simulation of the ureter: effects of the model parameters on ureteral pressure/flow relations

Ureteral peristaltic mechanism facilitates urine transport from the kidney to the bladder. Numerical analysis of the peristaltic flow in the ureter aims to further our understanding of the reflux phenomenon and other ureteral abnormalities. Fluid-structure interaction (FSI) plays an important role in accuracy of this approach and the arbitrary Lagrangian-Eulerian (ALE) formulation is a strong method to analyze the coupled fluid-structure interaction between the compliant wall and the surrounding fluid. This formulation, however, was not used in previous studies of peristalsis in living organisms. In the present investigation, a numerical simulation is introduced and solved through ALE formulation to perform the ureteral flow and stress analysis. The incompressible Navier-Stokes equations are used as the governing equations for the fluid, and a linear elastic model is utilized for the compliant wall. The wall stimulation is modeled by nonlinear contact analysis using a rigid contact surface since an appropriate model for simulation of ureteral peristalsis needs to contain cell-to-cell wall stimulation. In contrast to previous studies, the wall displacements are not predetermined in the presented model of this finite-length compliant tube, neither the peristalsis needs to be periodic. Moreover, the temporal changes of ureteral wall intraluminal shear stress during peristalsis are included in our study. Iterative computing of two-way coupling is used to solve the governing equations. Two phases of nonperistaltic and peristaltic transport of urine in the ureter are discussed. Results are obtained following an analysis of the effects of the ureteral wall compliance, the pressure difference between the ureteral inlet and outlet, the maximum height of the contraction wave, the contraction wave velocity, and the number of contraction waves on the ureteral outlet flow. The results indicate that the proximal part of the ureter is prone to a higher shear stress during peristalsis compared with its middle and distal parts. It is also shown that the peristalsis is more efficient as the maximum height of the contraction wave increases. Finally, it is concluded that improper function of ureteropelvic junction results in the passage of part of urine back flow even in the case of slow start-up of the peristaltic contraction wave.     

Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2^+/−;Emx2^+/− mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2^+/−;Emx2^+/− embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.     

Pharmacology of ureter.

Ureter which performs the important function of transport of urine from kidney to the bladder is not a passive tube, but exhibits characteristic spontaneous (peristaltic) activity. This peristaltic activity is characterized by coordinated muscular contractions, which after originating from a spontaneously active primary pacemaker, situated in the vicinity of the pelvi ureteric junction, propagate downwards along the entire length of the ureter. In addition, the ureter, like the heart, possesses certain cells which become activated when the primary pacemaker is suppressed or there is an interruption of conduction, thereby, acting as latent pacemakers. (1) The peristaltic activity of the ureter is modified by several pharmacologically active substances. Moreover, some of these substances are occasionally able to initiate spontaneous activity even in quiescent ureters. This article briefly reviews the effects of catecholamines (adrenaline, noradrenaline and isoprenaline) and acetylcholine on the ureters of human beings and some domestic and laboratory animals.     

Effects of stent stiffness on local haemodynamics with particular reference to wave reflections

The placement of a rigid stent within an elastic vessel produces wave reflection sites at the entrance to and exit from the stent. The net haemodynamic effects of these reflections depend critically on the degree of stiffness of the stent and on its length and position within the diseased vessel, variables that have been found to affect the clinical performance of a stent. Here these effects are examined analytically, using a segmented tube model. The results indicate that the presence of the stent within the larger diseased vessel has the effect of producing higher pressure at the vessel entrance than that at exit. This pressure difference, when superimposed on the underlying pressure distribution within the vessel, has the net effect of actually aiding rather than impeding the flow, but the extent of this depends on the length and position of the stent. A short stent placed near the entrance of the diseased vessel may be favoured clinically for producing the least perturbation in the underlying haemodynamics and thus reducing the chance of restenosis, while a long stent placed near the exit may be favoured for producing a positive pressure difference and thus aiding the flow.     

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.     

Management of vesicoureteral reflux

Four cases of vesicoureteral reflux are discussed by prominent pediatric urologists. The condition can range from minimal reflux into the distal ureter to massive reflux causing tortuosity of the ureter and hydronephrosis. Treatment options range from medical management to tapering of the ureter with reimplantation. The cross-trigonal technique is popular among pediatric urologists, and the Politano-Leadbetter technique is a very successful technique that has stood the test of time. The extravesical approach to ureteral reimplantation reduces morbidity, shortens hospital stays, reduces medical costs, and maintains the high success rates of the intravesical techniques. Subureteric injection of bulking agents to correct the reflux holds promise as an alternative to open surgery, but presents the challenge of identifying the ideal bulking agent.     

A novel antireflux device based on magnets

BACKGROUND: The problem of eliminating gastroesophageal reflux (GER) with simple, effective and devoid of unpleasant side effects procedures is still unresolved. We tried to settle this problem with a magnetic device that should be applied to the distal end of the esophagus. MATERIALS AND METHODS: Two plastoferrite magnets of 2 x 4 x 0.5cm(1) were applied, on the opposite sides of a flaccid polyethylene tube mimicking the physical characteristics of the terminal esophagus. The two magnets attracting themselves compressed the tube, creating an artificial high-pressure zone that divided the tube in two segments. Both segments of the tube were connected to pressure transducers and a polygraph and one of them was connected to a hydraulic pump. The pressure was progressively increased in this segment up to a value sufficient to detach the magnets with consequent flowing of the water in the other segment of the tube. RESULTS: The progressive increase of the pressure in a segment of the tube detached the magnets allowing a free flow into the other segment when the pressure reached an average value of 9.75+/-1.05 mmHg (mean+/-SD). CONCLUSIONS: A couple of magnets clamping a tube with the characteristics of the distal esophagus is able to prevent the passage of liquid with a pressure value near to that of a normal lower esophageal sphincter. This magnetic device could be useful to maintain closed a sphincter unable to prevent gastroesophageal reflux.     

Cascade Bioassay Evidence for the Existence of Urothelium-Derived Inhibitory Factor in Guinea Pig Urinary Bladder

Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intact or -denuded guinea pig urinary bladders were used as donor tissues, stimulated by intermittent application of carbachol before or during the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), the adenosine/P1 nucleoside receptor antagonist 8-(p-sulfophenyl)theophylline (8-PST) or the cyclo-oxygenase inhibitor diclofenac infused to bath donor and bioassay tissues. The spontaneous contractions of bioassay ureters were unaltered by application of carbachol 1–5 µM in the presence of scopolamine 5–30 µM. When carbachol was applied over the urothelium-denuded bladder, the assay ureter contraction rate was unaltered. Introducing carbachol over the everted urothelium-intact bladder significantly inhibited the contraction frequency of the assay ureter, suggesting the transfer of an inhibitory activity from the bladder to the assay ureter. The transmissible inhibitory activity was not markedly antagonized by L-NAME, 8-PST or diclofenac, while L-NAME nearly abolished nitrite release from the urothelium-intact bladder preparations. We suggest that urothelium-derived inhibitory factor is a transmissible entity over a significant distance as demonstrated in this novel cascade superfusion assay and seems less likely to be nitric oxide, nitrite, an adenosine receptor agonist or subject to inhibition by administration of a cyclo-oxygenase inhibitor.     

Water extrusion in the trap bladders ofUtricularia vulgaris

In the trap bladder ofUtricularia vulgaris, a sudden expansion (convex bladder) by opening of the entrance door upon stimulus was followed by slow decreases in bladder width and internal hydrostatic pressure. The decreases were caused by continuous water outflow from bladder lumen. The bladder reached initial resetting state (concave bladder) in about 30 min. The internal pressure reduced to 0.86 bar. This reduction was inhibited by application of sodium azide in the bladder lumen. The total water outflow for 30 min from a bladder, measured using a glass capillary inserted in the bladder, was 630 nl: the rate was 21 nl/min. This rate was also inhibited by sodium azide. In bladder resetting under paraffin oil, it was observed that water emerges from near the free edge of the trap door. From light and electron microscopic observations of the entrance region, it is concluded that the inlet of water outflow is the bifid trichomes which stand on the inner surface of the bladder near the entrance, and the outlet is the outer and middle zones of the pavement epithelium, or threshold, against which the free edge of the door rests.     

Characterization of spontaneous electrical activity of the urinary tract: Ureter,bladder, urethra

The study aimed to characterize spontaneous electrical activity of the ureter, urinary bladder and urethra as well as their interrelationship. The basic parameters of pacemaker activity (amplitude, frequency, peak rise rate, peak rise time, peak half-width) were comparatively analyzed in each of the active areas. Out of the three areas compared, the ureteral rhythmogenic zone displayed the maximum amplitude and apex formation rate. Under conditions of urine influx from the ureter into the bladder and isolation of these organs from the urethra, the amplitude and peak rise rate in the latter decreased by almost 20%. At the same time, all the parameters of the ureter and bladder remained intact. Complete block of urine influx into the bladder by transecting the ureter at the appropriate area led to a slight decrease in the amplitude of action potentials, peak rise rate and rhythmogenicity frequency in the bladder, respectively, by 14.2, 12.5 and 16% at the constancy of other parameters of its activity. Subsequent isolation of the bladder from the urethra had no appreciable effect on the altered parameters of the former. The similar tendency towards a reduction of the parameters was observed under the same conditions in the urethra. Thus, a relationship was revealed between autonomous activities of the ureter, bladder and urethra. The regulatory role in this process is provided by the urine flow through these organs.     

An experimental model of ascending pyelonephritis due toCandida albicans in rats

We developed a new experimental model of ascendingCandida pyelonephritis in female rats with leukopenia and vesicoureteral reflux. Rats were treated transperitoneally with cyclophosphamide (200 mg/kg) to induce leukopenia 3 days before and transurethrally with diluted acetic acid solution to induce vesicoureteral reflux 1 day before inoculation ofCandida albicans strain, ATCC 10259 (containing 10⁷ cells). Microscopy revealed acute pyelonephritis in whichCandida cells invaded from the fornix and/or papilla into the medulla within 3 days after inoculation. Between 7 and 28 days after inoculation, chronic pyelonephritis reached the cortex. The incidence of pyelonephritis increased gradually and was approximately 80% after 7 days.Candida colony counts of bladder urine specimens obtained by direct puncture were significantly greater in rats with pyelonephritis extending into the parenchyma than in those with pyelonephritis located along the pelvis (p<0.01). These results suggest that this rat model shows the characteristic feature of ascending pyelonephritis due toC. albicans and that the severity ofCandida pyelonephritis can be estimated fromCandida counts of bladder urine.