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Concept: Ureter

205

Background The epidemiologic characteristics of children and young adults with acute kidney injury have been described in single-center and retrospective studies. We conducted a multinational, prospective study involving patients admitted to pediatric intensive care units to define the incremental risk of death and complications associated with severe acute kidney injury. Methods We used the Kidney Disease: Improving Global Outcomes criteria to define acute kidney injury. Severe acute kidney injury was defined as stage 2 or 3 acute kidney injury (plasma creatinine level ≥2 times the baseline level or urine output <0.5 ml per kilogram of body weight per hour for ≥12 hours) and was assessed for the first 7 days of intensive care. All patients 3 months to 25 years of age who were admitted to 1 of 32 participating units were screened during 3 consecutive months. The primary outcome was 28-day mortality. Results A total of 4683 patients were evaluated; acute kidney injury developed in 1261 patients (26.9%; 95% confidence interval [CI], 25.6 to 28.2), and severe acute kidney injury developed in 543 patients (11.6%; 95% CI, 10.7 to 12.5). Severe acute kidney injury conferred an increased risk of death by day 28 after adjustment for 16 covariates (adjusted odds ratio, 1.77; 95% CI, 1.17 to 2.68); death occurred in 60 of the 543 patients (11.0%) with severe acute kidney injury versus 105 of the 4140 patients (2.5%) without severe acute kidney injury (P<0.001). Severe acute kidney injury was associated with increased use of mechanical ventilation and renal-replacement therapy. A stepwise increase in 28-day mortality was associated with worsening severity of acute kidney injury (P<0.001 by log-rank test). Assessment of acute kidney injury according to the plasma creatinine level alone failed to identify acute kidney injury in 67.2% of the patients with low urine output. Conclusions Acute kidney injury is common and is associated with poor outcomes, including increased mortality, among critically ill children and young adults. (Funded by the Pediatric Nephrology Center of Excellence at Cincinnati Children's Hospital Medical Center and others; AWARE ClinicalTrials.gov number, NCT01987921 .).

Concepts: Ureter, Renal physiology, Renal failure, Odds ratio, Urine, Nephrology, Kidney, Epidemiology

171

Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

Concepts: Ureter, Endocrine system, Renal pelvis, Kidney, Extracellular matrix, Renin-angiotensin system, Chronic kidney disease, Blood pressure

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

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

67

Pathogens often inhabit the body asymptomatically, emerging to cause disease in response to unknown triggers. In the bladder, latent intracellular Escherichia coli reservoirs are regarded as likely origins of recurrent urinary tract infection (rUTI), a problem affecting millions of women worldwide. However, clinically plausible triggers that activate these reservoirs are unknown. Clinical studies suggest that the composition of a woman’s vaginal microbiota influences her susceptibility to rUTI, but the mechanisms behind these associations are unclear. Several lines of evidence suggest that the urinary tract is routinely exposed to vaginal bacteria, including Gardnerella vaginalis, a dominant member of the vaginal microbiota in some women. Using a mouse model, we show that bladder exposure to G. vaginalis triggers E. coli egress from latent bladder reservoirs and enhances the potential for life-threatening outcomes of the resulting E. coli rUTI. Transient G. vaginalis exposures were sufficient to cause bladder epithelial apoptosis and exfoliation and interleukin-1-receptor-mediated kidney injury, which persisted after G. vaginalis clearance from the urinary tract. These results support a broader view of UTI pathogenesis in which disease can be driven by short-lived but powerful urinary tract exposures to vaginal bacteria that are themselves not “uropathogenic” in the classic sense. This “covert pathogenesis” paradigm may apply to other latent infections, (e.g., tuberculosis), or for diseases currently defined as noninfectious because routine culture fails to detect microbes of recognized significance.

Concepts: Ureter, Gut flora, Urine, Kidney, Bacteria, Urinary tract infection, Escherichia coli

37

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

28

Fluoride compounds are abundant and widely distributed in the environment at a variety of concentrations. Further, fluoride induces toxic effects in target organs such as the liver and kidney. In this study, we performed an early analysis of renal function using a clearance technique in Wistar rats acutely exposed to fluoride at a plasma concentration of 0.625 μg/ml. Our results revealed that fluoride, at a concentration close to the concentration present in the serum after environmental exposure, induced a significant tubular dysfunction, resulting in diluted urine, impaired protein reabsorption, and increased calcium and phosphate urinary excretion. Our work demonstrates that even acute exposures to low concentrations of NaF may induce renal damage and confirms that, after exposure, the kidney participates directly in the calcium and phosphate deficiencies observed in fluoride-exposed populations.

Concepts: Urine, Renal failure, Electrolyte, Ureter, Nephrology, Fluoride, Renal physiology, Kidney

28

Morphological changes that occur during kidney injury involve actin skeleton remodeling. Here we tested whether heat-shock protein 27 (HSP27), a small stress response protein involved in cytoskeletal remodeling, protects the kidney from tubulointerstitial fibrosis in obstructive nephropathy. Tubular cell HSP27 immunostaining was significantly increased in human kidneys with ureteropelvic junction obstruction, supporting the clinical relevance of our studies. To develop an animal model for mechanistic studies, we generated transgenic mice that specifically overexpress human HSP27 in renal tubules, under the kidney androgen-regulated protein promoter, and determined the effects of HSP27 overexpression on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis following unilateral ureteral obstruction. This was associated with decreased fibrogenesis as evidenced by significant declines in phosphorylated p38MAPK, collagen III, α-smooth muscle actin, 4-hydroxynonenal, and reduced trichrome staining following obstruction. Notably, E-cadherin and β-catenin remained at the cell membrane of tubular cells in transgenic mice with an obstructed ureter. Monocyte/macrophage infiltration, however, was not significantly affected in these transgenic mice. Thus, tubular HSP27 inhibits fibrogenesis in obstructive nephropathy. Further studies are needed to determine pathways regulating the interactions between HSP27 and the E-cadherin-β-catenin complex.

Concepts: Urinary bladder, Actin, Gene expression, Gene, Renal artery, Protein, Ureter, Kidney

28

What’s known on the subject? and What does the study add? Chronic urinary retention (CUR) is a poorly defined entity, as the key element of definition, significant postvoid residual urine volume (PVR), has not a worldwide and moreover evidenced-based definition. There is no agreement on which is the threshold value to define a significant PVR and different society produced guidelines with different thresholds ranging from 300 mL to 1000 mL. Diagnosis is difficult, and management has not been defined yet. There is a lack of studies on the best management of these patients, as this group of patients has always been considered at high risk of failure. Only one study compares conservative with the surgical management but it is not a randomised controlled trail. This review offers a systematic appraisal of the most recent publications on CUR. It indicates the absence of a real worldwide agreed definition, as the two keys element of it are not satisfactorily defined yet: significant PVR, is suffering from a lack of evidenced-based definition, and percussable or palpable bladder is a very nebulous concept as it is not a criteria of certainty as different individual variables affect it. This has an important effect on management which is not structured. Most of the trials involving benign prostatic hyperplasia treatments (either medical or surgical) tend to exclude this group of patients, which is a clinically important group, comprising up to a quarter of men undergoing TURP in the UK. Urinary retention describes a bladder that does not empty completely or does not empty at all. Historically, urinary retention has been classified as either acute or chronic the latter is generally classified as high pressure or low pressure according to the bladder filling pressure on urodynamic. A MEDLINE® search for articles written in English and published before January 2010 was done using a list of terms related to urinary retention: ‘urinary retention’, ‘chronic urinary retention’ and ‘PVR’. Chronic urinary retention (CUR) is defined by the International Continence Society as ‘a non-painful bladder, which remains palpable or percussable after the patient has passed urine’. Abrams was the first to choose a residual urine volume >300 mL to define CUR as he considered it the minimum volume at which the bladder becomes palpable suprapubically. The UK National Institute for Health and Clinical Excellence lower urinary tract symptoms (LUTS) guidelines define CUR as a postvoid residual urine volume (PVR) of >1000 mL. No studies have specifically addressed the problem of quantifying the minimum amount of urine present in the bladder to define CUR. Nor did we find any publications objectively assessing at what amount of urine a bladder can be palpable. The ability to feel a bladder may rely on variables (i.e. medical skills and patient habitus). There is a marked variability of PVR, so the test should be repeated to improve precision. As defining CUR is difficult, structured management is challenging. Nearly all prospective trials exclude men with CUR from analysis, possibly anticipating a poor outcome and a high risk of complications. However, men with CUR are a clinically important group, comprising up to 25% of men undergoing transurethral resection of the prostate. Definition of CUR is imprecise and arbitrary. Most studies seem to describe the condition as either a PVR of >300 mL in men who are voiding, or >1000 mL in men who are unable to void. This confusion leads to an inability to design and interpret studies; indeed most prospective trials simply exclude these patients. There is a clear need for internationally accepted definitions of retention to allow both treatment and reporting of outcomes in men with LUTS, and for such definitions to be used by all investigators in future trials.

Concepts: Ureter, Urinary system, Urine, Urinary retention, Urinary bladder, Prostatic stent, Urology

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To evaluate the efficacy of laparoscopic pneumovesical ureter reimplantation for congenital malformation involving the vesicoureteral junction in children.

Concepts: Junction, Texas, Ureter, Developmental biology, Centers for Disease Control and Prevention, Congenital abnormality, Congenital disorders, Congenital, Congenital disorder