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Concept: Urinary system

168

BACKGROUND: To investigate the effect of prostaglandin depletion by means of COX-inhibition on cholinergic enhanced spontaneous contractions. METHODS: The urethra and bladder of 9 male guinea pigs (weight 270–300 g) were removed and placed in an organ bath with Krebs' solution. A catheter was passed through the urethra through which the intravesical pressure was measured. The muscarinic agonist arecaidine, the non-selective COX inhibitor indomethacin, and PGE2 were subsequently added to the organ bath. The initial average frequency and amplitude of spontaneous contractions in the first 2 minutes after arecaidine application were labelled Fini and Pini, respectively. The steady state frequency (Fsteady) and amplitude (Psteady) were defined as the average frequency and amplitude during the 5 minutes before the next wash out. RESULTS: Application of 1 muM PGE2 increased the amplitude of spontaneous contractions without affecting frequency. 10 muM of indomethacin reduced amplitude but not frequency.The addition of indomethacin did not alter Fini after the first application (p = 0.7665). However, after the second wash, Fini was decreased (p = 0.0005). Fsteady, Psteady and Pini were not significantly different in any of the conditions. These effects of indomethacin were reversible by PGE2 addition.. CONCLUSIONS: Blocking PG synthesis decreased the cholinergically stimulated autonomous contractions in the isolated bladder. This suggests that PG could modify normal cholinergically evoked response. A combination of drugs inhibiting muscarinic receptors and PG function or production can then become an interesting focus of research on a treatment for overactive bladder syndrome.

Concepts: Urine, Urology, Urinary bladder, Urinary system, Urethra, Ureter, Urogenital sinus, Guinea pig

168

BACKGROUND: Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease. METHODS: UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys. RESULTS: Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney’s peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period. CONCLUSIONS: Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.

Concepts: Kidney, Urinary system, Ureter, Renal artery, Renal vein, Hydronephrosis

154

Cranberry consumption has shown prophylactic effects against urinary tract infections (UTI), although the mechanisms involved are not completely understood. In this paper, cranberry phenolic compounds and their potential microbial-derived metabolites (such as simple phenols and benzoic, phenylacetic and phenylpropionic acids) were tested for their capacity to inhibit the adherence of uropathogenic Escherichia coli (UPEC) ATCC®53503™ to T24 epithelial bladder cells. Catechol, benzoic acid, vanillic acid, phenylacetic acid and 3,4-dihydroxyphenylacetic acid showed anti-adhesive activity against UPEC in a concentration-dependent manner from 100-500 µM, whereas procyanidin A2, widely reported as an inhibitor of UPEC adherence on uroepithelium, was only statistically significant (p < 0.05) at 500 µM (51.3% inhibition). The results proved for the first time the anti-adhesive activity of some cranberry-derived phenolic metabolites against UPEC in vitro, suggesting that their presence in the urine could reduce bacterial colonization and progression of UTI.

Concepts: Kidney, Urinary tract infection, Urine, Escherichia coli, Urinary bladder, Urinary system, Catechin, Vanillin

154

INTRODUCTION Dyscalcemia is associated with adverse cardiovascular effects. Therapy of heart failure (HF) may change serum calcium by reduction of urinary wasting or increased calcium apposition to bones.  OBJECTIVES Our objectives were to assess the prevalence of dyscalcemia in patients with newly up-titrated HF therapy, to explore clinical and laboratory determinants of abnormal serum calcium levels and to analyze the relation of dyscalcemia to prognosis. PATIENTS AND METHODS In 722 HF patients (age 53 ± 10 years, 13% female, NYHA class III-IV) naïve to HF drugs, we have assessed crude prevalence of serum dyscalcemia and adjusted risk of calcium abnormalities on top of recommended therapy and analysed the association of calcium abnormalities with mortality at 2 years of follow-up. RESULTS During therapy up-titration NYHA class improved in 66.7% patients, in 31.0% did not change and worsened in 2.4%. Hypocalcemia occurred in 166 (23.0%) patients and was more prevalent in patients who became less symptomatic on target HF therapy. ypercalcemia was diagnosed in 63 (8.7%) patients and predominated in those who did not respond to treatment. These findings were independent of kidney function, BMI, HF ethiology, thiazides use, age and sex. Hypercalcemia was associated with more catabolic profile, hemodynamic compromise, inflammation and lower bone mineral density. Lower albumin, higher serum phosphorus, were independently of kidney function significant predictors of hypercalcemia.  Hypocalcemia was associated with less catabolism, higher albumin, lower phosphorus, treatment of thiazides, smoking history. Neither hypocalcemia nor hypercalcemia affected prognosis.  CONCLUSIONS We concluded that serum dyscalcemia is related to response to HF therapy and HF severity on top of treatment. Mild hypocalcemia is associated with clinical improvement and does not worsen HF outcome. Hypercalcemia occurs more frequently in non-responders to therapy, its clinical significance requires further studies.  

Concepts: Kidney, Bone, Vitamin D, Medical statistics, Calcium, Urinary system, Prevalence, Calcium metabolism

113

Interstitial cystitis/bladder pain syndrome (IC) is a multifactorial syndrome of severe pelvic and genitalia pain and compromised urinary function; a subset of IC patients present with Hunner’s lesions or ulcers on their bladder walls (UIC). UIC is diagnosed by cystoscopy, which may be quite painful. The objective of this study was to determine if a calculated Bladder Permeability Defect Risk Score (BP-RS) based on non-invasive urinary cytokines could discriminate UIC patients from controls and IC patients without Hunner’s ulcers.

Concepts: Medical terms, Urology, Urinary incontinence, Urinary bladder, Urinary system, Pain, Cystitis, Interstitial cystitis

46

Many urological studies rely on models of animals, such as rats and pigs, but their relation to the human urinary system is poorly understood. Here, we elucidate the hydrodynamics of urination across five orders of magnitude in body mass. Using high-speed videography and flow-rate measurement obtained at Zoo Atlanta, we discover that all mammals above 3 kg in weight empty their bladders over nearly constant duration of 21 ± 13 s. This feat is possible, because larger animals have longer urethras and thus, higher gravitational force and higher flow speed. Smaller mammals are challenged during urination by high viscous and capillary forces that limit their urine to single drops. Our findings reveal that the urethra is a flow-enhancing device, enabling the urinary system to be scaled up by a factor of 3,600 in volume without compromising its function. This study may help to diagnose urinary problems in animals as well as inspire the design of scalable hydrodynamic systems based on those in nature.

Concepts: Blood, Urine, Mass, Urinary bladder, Urinary system, Urethra, Urination, Fluid mechanics

36

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Concepts: DNA, Kidney, Gene, Genetics, Urine, Urinary bladder, Urinary system, Ureter

30

Treatment of bacterial infections is becoming a serious clinical challenge due to the global dissemination of multidrug antibiotic resistance, necessitating the search for alternative treatments to disarm the virulence mechanisms underlying these infections. UropathogenicEscherichia coli(UPEC) employs multiple chaperone-usher pathway pili tipped with adhesins with diverse receptor specificities to colonize various host tissues and habitats. For example, UPEC F9 pili specifically bind galactose orN-acetylgalactosamine epitopes on the kidney and inflamed bladder. Using X-ray structure-guided methods, virtual screening, and multiplex ELISA arrays, we rationally designed aryl galactosides andN-acetylgalactosaminosides that inhibit the F9 pilus adhesin FmlH. The lead compound, 29β-NAc, is a biphenylN-acetyl-β-galactosaminoside with aKiof ∼90 nM, representing a major advancement in potency relative to the characteristically weak nature of most carbohydrate-lectin interactions. 29β-NAc binds tightly to FmlH by engaging the residues Y46 through edge-to-face π-stacking with its A-phenyl ring, R142 in a salt-bridge interaction with its carboxylate group, and K132 through water-mediated hydrogen bonding with its N-acetyl group. Administration of 29β-NAc in a mouse urinary tract infection (UTI) model significantly reduced bladder and kidney bacterial burdens, and coadministration of 29β-NAc and mannoside 4Z269, which targets the type 1 pilus adhesin FimH, resulted in greater elimination of bacteria from the urinary tract than either compound alone. Moreover, FmlH specifically binds healthy human kidney tissue in a 29β-NAc-inhibitable manner, suggesting a key role for F9 pili in human kidney colonization. Thus, these glycoside antagonists of FmlH represent a rational antivirulence strategy for UPEC-mediated UTI treatment.

Concepts: Immune system, Kidney, Bacteria, Urinary tract infection, Urine, Urinary bladder, Urinary system, Ureter

28

Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro-nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase-positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Concepts: Urology, Urinary incontinence, Urinary bladder, Urinary system, Urethra, Urination, Hyperplasia, Hypertrophy

28

We describe a novel infection-responsive coating for urinary catheters that provides a clear visual early warning of Proteus mirabilis infection and subsequent blockage. The crystalline biofilms of P. mirabilis can cause serious complications for patients undergoing long-term bladder catheterisation. Healthy urine is around pH 6, bacterial urease increases urine pH leading to the precipitation of calcium and magnesium deposits from the urine, resulting in dense crystalline biofilms on the catheter surface that blocks urine flow. The coating is a dual layered system in which the lower poly(vinyl alcohol) layer contains the self-quenching dye carboxyfluorescein. This is capped by an upper layer of the pH responsive polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit S100®). Elevation of urinary pH (>pH 7) dissolves the Eudragit layer, releasing the dye to provide a clear visual warning of impending blockage. Evaluation of prototype coatings using a clinically relevant in vitro bladder model system demonstrated that coatings provide up to 12h advanced warning of blockage, and are stable both in the absence of infection, and in the presence of species that do not cause catheter blockage. At the present time, there are no effective methods to control these infections or provide warning of impending catheter blockage.

Concepts: Present, Time, Bacteria, Urine, Urinary system, Urease, Urinary catheterization, Proteus mirabilis