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.     

Flow of urine through the ureter: a collapsible, muscular tube undergoing peristalsis

In steady flow through nonuniform collapsible tubes a key concept is the compressive zone, at which flow limitation can occur at both high and low Reynolds numbers. Ureteral peristalsis can be considered as a series of compressive zones, corresponding to waves of active muscular contraction, that move at near-constant speed along the ureter towards the bladder. One-dimensional, lubrication-theory analysis shows that peristalsis can pump urine from kidney into the bladder only at relatively low mean rates of urine flow. Under these circumstances isolated boluses of urine are propelled steadily through the ureter (assumed uniform) by the contraction waves. At higher mean rates of flow the behavior depends on whether the frequency of peristalsis is higher or lower than a critical value. For frequencies above the critical value steady propagation of boluses that are in contact with contraction waves at both ends is possible. As the flow rate rises the urine begins to leak through the contraction waves and steady peristaltic flow breaks down. There is an upper limit to the mean flow rate that can be carried by steady peristalsis, which depends on the mechanical properties of the ureter. At high flow rates the peristaltic contractions do not pump but hinder the flow of urine through the ureter.     

Development and differentiation of the ureteric bud into the ureter in the absence of a kidney collecting system

Six1-/- mice were found to have apparently normal ureters in the absence of a kidney, suggesting that the growth and development of the unbranched ureter is largely independent of the more proximal portions of the UB which differentiates into the highly branched renal collecting system. Culture of isolated urinary tracts (from normal and mutant mice) on Transwell filters was employed to study the morphogenesis of this portion of the urogenital system. Examination of the ureters revealed the presence of a multi-cell layered tubule with a lumen lined by cells expressing uroplakin (a protein exclusively expressed in the epithelium of the lower urinary tract). Cultured ureters of both the wild-type and Six1 mutant become contractile and undergo peristalsis, an activity preceded by the expression of alpha-smooth muscle actin (alphaSMA). Treatment with a number of inhibitors of signaling molecules revealed that inhibition of PI3 kinase dissociates the developmental expression of alphaSMA from ureter growth and elongation. Epidermal growth factor also perturbed smooth muscle differentiation in culture. Moreover, the peristalsis of the ureter in the absence of the kidney in the Six1-/- mouse indicates that the development of this clinically important function of ureter (peristaltic movement of urine) is not dependent on fluid flow through the ureter. In keeping with this, isolated ureters cultured in the absence of surrounding tissues elongate, differentiate and undergo peristalsis when cultured on a filter and undergo branching morphogenesis when cultured in 3-dimensional extracellular matrix gels in the presence of a conditioned medium derived from a metanephric mesenchyme (MM) cell line. In addition, ureters of Six1-/- urinary tracts (i.e., lacking a kidney) displayed budding structures from their proximal ends when cultured in the presence of GDNF and FGFs reminiscent of UB budding from the wolffian duct. Taken together with the above data, this indicates that, although the distal ureter (at least early in its development) retains some of the characteristics of the more proximal UB, the growth and differentiation (i.e., development of smooth muscle actin, peristalsis and uroplakin expression) of the distal non-branching ureter are inherent properties of this portion of the UB, occurring independently of detectable influences of either the undifferentiated MM (unlike the upper portion of the ureteric bud) or more differentiated metanephric kidney. Thus, the developing distal ureter appears to be a unique anatomical structure which should no longer be considered as simply the non-branching portion of the ureteric bud. In future studies, the ability to independently analyze and study the portion of the UB that becomes the renal collecting system and that which becomes the ureter should facilitate distinguishing the developmental nephrome (renal ontogenome) from the ureterome.     

Malignant Pheochromocytoma of the Organ of Zuckerkandl Requiring Aortic and Vena Caval Reconstruction

ObjectiveTo describe a case of a malignant pheochromocytoma located in the organ of Zuckerkandl that required aortic and vena caval resection and reconstruction.MethodsWe present a case report that includes clinical, laboratory, and radiographic data as well as photographs, results from pathology, and a brief review of the literature.ResultsA 46-year-old man was referred for evaluation of a 1.4-cm left adrenal mass incidentally discovered on an abdominopelvic computed tomography (CT) scan. Subsequent laboratory evaluation revealed the following values: urine norepinephrine, 252 [μg/24 h; urine normetanephrine, 1122 [μg/24 h; urine metanephrine, 162 μg/24 h; urine epinephrine, 7 [μg/24 h; urine vanillylman-delic acid, 8 mg/24 h; and plasma metanephrine, 98 pg/ mL. Imaging characteristics of the left adrenal mass were consistent with a benign adenoma, but CT also demonstrated a hypervascular paraaortic mass. ¹²³I-metaiodo-benzylguanidine scanning with fusion CT imaging demonstrated increased radiopharmaceutical uptake within the para-aortic mass consistent with a paraganglioma in the organ of Zuckerkandl. Findings from CT angiography of the abdomen and pelvis suggested aortic involvement and vena caval thrombus. The mass was excised en bloc, including portions of the aorta, inferior vena cava, and right ureter. The aorta and vena cava were reconstructed using Dacron grafts. The remaining right ureter and kidney were removed to avoid the possibility of a urine leak from an ureteroureterostomy. Final pathologic and operative findings confirmed a malignant pheochromocytoma of the organ of Zuckerkandl with invasion into the wall of the inferior vena cava and tumor thrombus extending into the lumen.ConclusionMalignant pheochromocytoma of the organ of Zuckerkandl involving the aorta and inferior vena cava is exceedingly rare, and although surgical resection and reconstruction can be radical and aggressive, this treatment offers the only chance for cure. (Endocr Pract. 2007;13:493-497)     

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.     

腹部超声检查对新生儿坏死性小肠结肠炎的临床应用价值研究

目的:探究腹部超声检查对新生儿坏死性小肠结肠炎(NEC)的临床应用价值。方法:选取2009年1月-2016年12月我院收治116例患有NEC的新生儿作为本次研究的对象,依据修正Bell-NEC分级标准将之分为确诊组(n=50)和疑似组(n=66),再依据临床转归分为手术组(n=37)和内科治愈组(n=79),对比确诊组和疑似组的腹部超声与X线检查结果,以及内科治愈组和手术组的腹部超声与X线检查结果。结果:在确诊组和疑似组中,腹部超声对肠壁积气、门静脉积气的检出率均高于X线摄片(P0.05)。腹部超声还发现了肠道蠕动缓慢、肠道蠕动消失和腹腔积液;内科治愈组腹部超声对肠壁增厚、肠管扩张和腹腔积液的检出率低于手术组(P0.05);内科治愈组X线摄片对肠管扩张的检出率低于手术组(P0.05)。结论:腹部超声能够提高NEC的检出率,且对NEC的临床转归有较好的预测作用。     

The effect of ureteric stents on urine flow: Reflux

If the ureter becomes blocked, the resultant increased pressure may be relieved by inserting a double-J stent (a polymer tube, usually punctuated with holes). A major clinical problem associated with stent use is reflux (retrograde flow of urine from the bladder to the kidney), which may result in infections, scarring, and even renal failure. We develop a mathematical model, treating the ureter as an elastic tube and the stent as a permeable rigid tube within it. We investigate how the number of holes in the stent wall affects the total amount of reflux that occurs when bladder pressure rises, by considering the limits of a highly-permeable stent, and an impermeable stent. We find that, in the scenarios we consider, the highly-permeable stent gives rise to less total reflux than the impermeable one.Revised version: 8 August 2003     

A proteomic glimpse into human ureter proteome

Urine has evolved as one of the most important biofluids in clinical proteomics due to its noninvasive sampling and its stability. Yet, it is used in clinical diagnostics of several disorders by detecting changes in its components including urinary protein/polypeptide profile. Despite the fact that majority of proteins detected in urine are primarily originated from the urogenital (UG) tract, determining its precise source within the UG tract remains elusive. In this article, we performed a comprehensive analysis of ureter proteome to assemble the first unbiased ureter dataset. Next, we compared these data to urine, urinary exosome, and kidney mass spectrometric datasets. Our result concluded that among 2217 nonredundant ureter proteins, 751 protein candidates (33.8%) were detected in urine as urinary protein/polypeptide or exosomal protein. On the other hand, comparing ureter protein hits (48) that are not shown in corresponding databases to urinary bladder and prostate human protein atlas databases pinpointed 21 proteins that might be unique to ureter tissue. In conclusion, this finding offers future perspectives for possible identification of ureter disease‐associated biomarkers such as ureter carcinoma. In addition, the ureter proteomic dataset published in this article will provide a valuable resource for researchers working in the field of urology and urine biomarker discovery. All MS data have been deposited in the ProteomeXchange with identifier PXD002620 ( http://proteomecentral.proteomexchange.org/dataset/PXD002620 ).     

尿液诊断膀胱癌的研究进展

摘要：膀胱癌是临床常见的发生在泌尿系统的恶性肿瘤,该病的发病率呈现逐年升高的趋势,其复发率也相对较高。早期诊断和定期随访是保证膀胱癌患者长期生存的关键。对于膀胱癌的诊断以及患者的随访通常凭借膀胱镜检查或尿脱落细胞学的测定。然而,前者的检查费用较为昂贵,且属于有创诊断;后者则具有检查敏感性相对较低的特点,还存在较大程度受病理科诊断医生主观因素影响的局限,目前还没有尿液生物标志物可以替代传统的诊断方法。膀胱肿瘤具有广泛的异质性,不同的疾病表型具有不同的分子差异。因此,引入尿液生物标志物来诊断疾病,评估疾病的侵袭性、进展的风险、复发的可能性和预后具有重要的临床价值。本文总结了目前尿液所含生物标志物诊断膀胱癌的研究现状,并对此领域的主要研究进展进行综述。     

Increased Inlet Blood Flow Velocity Predicts Low Wall Shear Stress in the Cephalic Arch of Patients with Brachiocephalic Fistula Access

BackgroundAn autogenous arteriovenous fistula is the optimal vascular access for hemodialysis. In the case of brachiocephalic fistula, cephalic arch stenosis commonly develops leading to access failure. We have hypothesized that a contribution to fistula failure is low wall shear stress resulting from post-fistula creation hemodynamic changes that occur in the cephalic arch.MethodsTwenty-two subjects with advanced renal failure had brachiocephalic fistulae placed. The following procedures were performed at mapping (pre-operative) and at fistula maturation (8–32 weeks post-operative): venogram, Doppler to measure venous blood flow velocity, and whole blood viscosity. Geometric and computational modeling was performed to determine wall shear stress and other geometric parameters. The relationship between hemodynamic parameters and clinical findings was examined using univariate analysis and linear regression.ResultsThe percent low wall shear stress was linearly related to the increase in blood flow velocity (p < 0.01). This relationship was more significant in non-diabetic patients (p < 0.01) than diabetic patients. The change in global measures of arch curvature and asymmetry also evolve with time to maturation (p < 0.05).ConclusionsThe curvature and hemodynamic changes during fistula maturation increase the percentage of low wall shear stress regions within the cephalic arch. Low wall shear stress may contribute to subsequent neointimal hyperplasia and resultant cephalic arch stenosis. If this hypothesis remains tenable with further studies, ways of protecting the arch through control of blood flow velocity may need to be developed.     

Severely damaged kidneys possess multipotent renoprotective stem cells

Background aimsTissue-specific stem cells are a promising target for kidney regeneration, because it has been shown that they play a primary role in kidney repair. Several methods have been developed for the isolation of stem/progenitor cells from healthy kidneys but the existence of these cells in chronically damaged kidneys has not been noticed so far.MethodsA mouse model of chronic kidney failure was developed by ligation of the left ureter for 5 months, and then isolation of stem cells from this tissue as well as normal kidneys was attempted.ResultsWe found that multipotent stem cells could be isolated from both types of tissue. In addition, the cells isolated from damaged kidneys showed potential for homing to the site of injury and a renoprotective effect in an animal model of cisplatin-induced nephropathy.ConclusionsThese results show that multipotent renoprotective stem cells exist in severely damaged kidneys, which could be a target for designing new therapies.     

Influence of overlapping pattern of multiple overlapping uncovered stents on the local mechanical environment: A patient-specific parameter study

BackgroundMultiple overlapping uncovered stents (MOUS) system has shown potentials in managing complex aortic aneurysms with side branches involvement. It promotes the development of thrombus by modulating local flow pattern that reduces the wall tension, while maintaining patency of side branches. However the modulation of local hemodynamic parameters depends on various factors that have not been assessed comprehensively.MethodsAneurysm 3D geometry was reconstructed based on CT images. One-way fluid-structure interaction analysis was performed to quantify structural stress concentration in the wall, and changes of blood velocity, wall shear stress (WSS), oscillatory shear index (OSI), relative residence time (RRT) and pressure in the sac due to the stent deployment.ResultsHigh structural stress concentration due to stent deployment was found in the landing zone and it increased linearly with the number of stents deployed. The wall tension in the sac was unaffected by the stent deployment. Stress within the wall was insensitive to the different overlapping pattern. After one stent was deployed, the mean flow velocity in the sac reduced by 36.4%. The deployment of the 2nd stent further reduced the mean sac velocity by 10%. WSS decreased while both OSI and RRT increased after stent deployment, however pressure in the sac remained nearly unchanged. Except for the cases with complete stents struts alignment, different overlapping pattern had little effect on flow parameters.ConclusionsMechanical parameters modulated by the MOUS are insensitive to different overlapping pattern suggesting that endovascular procedure can be performed with less attention to the overlapping pattern.     

Human alpha defensin 5 expression in the human kidney and urinary tract

Background

The mechanisms that maintain sterility in the urinary tract are incompletely understood. Recent studies have implicated the importance of antimicrobial peptides (AMP) in protecting the urinary tract from infection. Here, we characterize the expression and relevance of the AMP human alpha-defensin 5 (HD5) in the human kidney and urinary tract in normal and infected subjects.

Methodology/Principal Findings

Using RNA isolated from human kidney, ureter, and bladder tissue, we performed quantitative real-time PCR to show that DEFA5, the gene encoding HD5, is constitutively expressed throughout the urinary tract. With pyelonephritis, DEFA5 expression significantly increased in the kidney. Using immunoblot analysis, HD5 production also increased with pyelonephritis. Immunostaining localized HD5 to the urothelium of the bladder and ureter. In the kidney, HD5 was primarily produced in the distal nephron and collecting tubules. Using immunoblot and ELISA assays, HD5 was not routinely detected in non-infected human urine samples while mean urinary HD5 production increased with E.coli urinary tract infection.

Conclusions/Significance

DEFA5 is expressed throughout the urinary tract in non-infected subjects. Specifically, HD5 is expressed throughout the urothelium of the lower urinary tract and in the collecting tubules of the kidney. With infection, HD5 expression increases in the kidney and levels become detectable in the urine. To our knowledge, our findings represent the first to quantitate HD5 expression and production in the human kidney. Moreover, this is the first report to detect the presence of HD5 in infected urine samples. Our results suggest that HD5 may have an important role in maintaining urinary tract sterility.     

Smad4 Regulates Ureteral Smooth Muscle Cell Differentiation during Mouse Embryogenesis

Proper formation of ureteral smooth muscle cells (SMCs) during embryogenesis is essential for ureter peristalsis that propels urine from the kidney to the bladder in mammals. Currently the molecular factors that regulate differentiation of ureteral mesenchymal cells into SMCs are incompletely understood. A recent study has reported that Smad4 deficiency reduces the number of ureteral SMCs. However, its precise role in the ureteral smooth muscle development remains largely unknown. Here, we used Tbx18:Cre knock-in mouse line to delete Smad4 to examine its requirement in the development of ureteral mesenchyme and SMC differentiation. We found that mice with specific deletion of Smad4 in Tbx18-expressing ureteral mesenchyme exhibited hydroureter and hydronephrosis at embryonic day (E) 16.5, and the mutant mesenchymal cells failed to differentiate into SMCs with increased apoptosis and decreased proliferation. Molecular markers for SMCs including alpha smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-MHC) were absent in the mutant ureters. Moreover, disruption of Smad4 significantly reduced the expression of genes, including Sox9, Tbx18 and Myocardin associated with SMC differentiation. These findings suggest that Smad4 is essential for initiating the SMC differentiation program during ureter development.     

Dependence of leukocyte capture on instantaneous pulsatile flow

Atherosclerosis, an artery disease, is currently the leading cause of death in the United States in both men and women. The first step in the development of atherosclerosis involves leukocyte adhesion to the arterial endothelium. It is broadly accepted that blood flow, more specifically wall shear stress (WSS), plays an important role in leukocyte capture and subsequent development of an atherosclerotic plaque. What is less known is how instantaneous WSS, which can vary by up to 5 Pa over one cardiac cycle, influences leukocyte capture. In this paper we use direct numerical simulations (DNS), performed using an in-house code, to illustrate that leukocyte capture is different whether as a function of instantaneous or time-averaged blood flow. Specifically, a stenotic plaque is modeled using a computational fluid dynamics (CFD) solver through fully three-dimensional Navier-Stokes equations and the immersed boundary method. Pulsatile triphasic inflow is used to simulate the cardiac cycle. The CFD is coupled with an agent-based leukocyte capture model to assess the impact of instantaneous hemodynamics on stenosis growth. The computed wall shear stress agrees well with the results obtained with a commercial software, as well as with theoretical results in the healthy region of the artery. The analysis emphasizes the importance of the instantaneous flow conditions in evaluating the leukocyte rate of capture. That is, the capture rate computed from mean flow field is generally underpredicted compared to the actual rate of capture. Thus, in order to obtain a reliable estimate, the flow unsteadiness during a cardiac cycle should be taken into account.     

The role of alpha-adrenoreceptors in the treatment of urological diseases

One of the most important clinical pharmacological invention in the last decades the role of adrenoreceptors in urological disease. The disorders of emptying the bladder are associated to the urology. Plant extracts efficacy is low, indicated only in mild symptoms, surgery has to be performed in advanced cases. Recognise, discovering the role of adrenoreceptors in the prostate, bladder neck has changed the treatment of benign prostatic hyperplasia. Relieving the muscle tension leads to a better urinary flow, decreased residual urine and less complaints. Combination with 5alpha-reductase inhibitor a better results can be achieved. The inflammation in prostate is a frequent disease of all age of males. Spasm of the bladder neck maintains the complaints additional alpha-blocker treatment combined with antibiotics, anti-inflammatory drugs are the best choice to cure the patients. Alpha-adrenergic receptor can be found in the lower part of ureter as well. To promote the spontaneous expulsion of lower ureter stones, or fragments after ESWL (extracorporal shock wave lithotripsy) the alpha-blockers are highly recommended.