Influence of sildenafil on blood oxygen saturation of the obstructed bladder.

BACKGROUND: Blood oxygen saturation (BOS) is decreased in a low-compliant, overactive obstructed bladder. The objective of this study is to determine the effect of Sildenafil (SC) on bladder function and BOS) in an in vivo animal model of bladder outlet obstruction. METHODS: Thirty-two guinea pigs; sham operated (n = 8), sham operated + SC (n = 8), urethrally obstructed (n = 8) and urethrally obstructed + SC (n = 8) were studied during an 8 week period. BOS of the bladder wall was measured by differential path-length spectroscopy (DPS) before obstruction, at day 0, and at week 8. The bladder function was evaluated by urodynamic studies every week. RESULTS: Before surgery and after sham operation all study parameters were comparable. After sham operation, bladder function and BOS did not change. In the obstructed group the urodynamic parameters were deteriorated and BOS was decreased. In the group obstruction + SC, bladder compliance remained normal and overactivity occurred only sporadic. BOS remained unchanged compared to the sham group and was significantly higher compared to the obstruction group. CONCLUSIONS: In an obstructed bladder the loss of bladder function is accompanied by a significant decrease in BOS. Treatment of obstructed bladders with SC yields a situation of high saturation, high bladder compliance and almost no overactivity. Maintaining the microcirculation of the bladder wall might result in better bladder performance without significant loss of bladder function. Measurement of BOS and interventions focussing on tissue microcirculation may have a place in the evaluation / treatment of various bladder dysfunctions.

Management of urinary stones: state of the art and future perspectives by experts in stone disease.

AIM: To present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the Experts in Stone Disease Congress in Valencia in January 2024. Options of treatment: The surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. For 1.5 cm renal stones, both m-PCNL and RIRS have proven to be valid treatment alternatives with comparable stone-free rates. The m-PCNL has proven to be more cost effective and requires a shorter operative time, while the RIRS has demonstrated lower morbidity in terms of blood loss and shorter recovery times. SWL has proven to be less effective at least for lower calyceal stones but has the highest safety profile. For a 6mm obstructing stone of the pelviureteric junction (PUJ) stone, SWL should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. RIRS has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. Technical issues of the surgical procedures for stone removal: In patients receiving antithrombotic therapy, SWL, PCN and open surgery are at elevated risk of hemorrhage or perinephric hematoma. URS, is associated with less morbidity in these cases. An individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. Pre-interventional urine culture and antibiotic therapy are mandatory although UTI treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. The use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. Measurements of temperature and pressure during RIRS are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. Ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. Topics of current research are the development of drug eluting and bioresorbable stents. Complications of endoscopic treatment: PCNL is considered the most invasive surgical option. Fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. Major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. Ureteroscopy causes less complications, although some of them can be severe. They depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). Diagnostic work up:  Genetic testing consents the diagnosis of monogenetic conditions causing stones. It should be carried out in children and in selected adults. In adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, APRT deficiency, and xanthinuria are excluded. A reliable stone analysis by infrared spectroscopy or X-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. The analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. Scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) is another fundamental research tool for the study of kidney stones. The combination of metagenomic analysis using Next Generation Sequencing (NGS) techniques and the enhanced quantitative urine culture (EQUC) protocol can be used to evaluate the urobiome of renal stone formers. Twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary pH with a digital pH meter. Urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. Urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. At the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. Patients should be evaluated for the association with systemic pathologies. PROPHYLAXIS: Personalized medicine and public health interventions are complementary to prevent stone recurrence. Personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. The more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. Primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. Renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. Stone analysis allows the identification of most "high-risk" patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). Patients at "high-risk" forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. Particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. FUTURE RESEARCH: Application of Artificial Intelligence are promising for automated identification of ureteral stones on CT imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. The synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation.

Changes in bladder wall blood oxygen saturation in the overactive obstructed bladder.

PURPOSE: Several studies suggest that hypoxia of the bladder wall contributes to bladder dysfunction but the exact relation between bladder function and blood oxygen saturation, a surrogate marker for hypoxia, is not known. We determined bladder wall blood oxygen saturation in vivo in an animal model of bladder outlet obstruction to establish the exact relation between blood oxygen saturation and bladder function. MATERIALS AND METHODS: In 8 sham operated and 8 urethrally obstructed guinea pigs we measured blood oxygen saturation of the bladder wall by differential path length spectroscopy before surgery and 8 weeks postoperatively. Urodynamic investigations performed during the whole 8-week period provided data on bladder function. RESULTS: Before surgery and 8 weeks after sham surgery blood oxygen saturation in the bladder wall was between 88% and 95% during filling. It decreased during voiding and returned to greater than 90% within 30 seconds. Eight weeks after obstruction saturation was significantly lower than in the sham operated group during filling and voiding. The decrease was positively related to bladder pressure during filling and voiding, and was more pronounced when overactivity was present. Local bladder contractions occurred without a measurable increase in bladder pressure but were associated with a decrease in saturation. CONCLUSIONS: A normal bladder maintains a high oxygen saturation level during filling. Bladder obstruction compromises this ability, especially when it involves overactivity. Local bladder contractions without a measurable increase in bladder pressure were associated with a decrease in blood saturation.

The preventive treatment of recurrent stone-formation: how can we improve compliance in the treatment of patients with recurrent stone disease?

Whether prevention of Urolithiasis is worthwhile is the outcome of the balance between efficacy of prevention and costs and efforts related of respectively prevention and treatment of a new stone. Well controlled trials demonstrate that effective prevention of new stone formation is possible using medical treatment and lifestyle interventions. In long-term general practice the results obtained with preventive interventions is disappointing. Low and diminishing long-term compliance to the intervention is a major cause for this. Both the long-term aspect and the natural resistance to lifestyle changes contribute to this low compliance. From an analysis of the existing data on trials of preventive interventions and from experiences obtained in other patient groups where lifestyle changes are applied I will make the case that self-empowerment of the patient using m-health lifestyle coaching (a smart phone application) can considerably enhance the level of prevention that is obtained in general practice. In conclusion, I will describe what features will improve usage and efficacy of such an app.

Modulators of urinary stone formation.

Urine contains compounds that modulate the nucleation, growth and aggregation of crystals as well as their attachment to renal epithelial cells. These compounds may function to protect the kidneys against: 1, the possibility of crystallization in tubular fluid and urine, which are generally metastable with respect to calcium salts, 2, crystal retention within the kidneys thereby preventing stone formation and 3, possibly against plaque formation at the nephron basement membrane. Since oxalate is the most common stone type, the effect of various modulators on calcium oxalate (CaOx) crystallization has been examined in greater details. Most of the inhibitory activity resides in macromolecules such as glycoproteins and glycosaminoglycans while nucleation promotion activity is most likely sustained by membrane lipids. Nephrocalcin, Tamm-Horsfall protein, osteopontin, urinary prothrombin fragment 1, and bikunin are the most studied inhibitory proteins while chondroitin sulfate (CS), heparan sulfate (HS) and hyaluronic acid (HA) are the best studied glycosaminoglycans. Crystallization modulating macromolecules discussed here are also prominent in cell injury, inflammation and recovery. Renal epithelial cells on exposure to oxalate and CaOx crystals produce some of the inflammatory molecules such as monocyte chemoattractant protein-1 (MCP-1) with no apparent role in crystal formation. In addition, macrophages surround the CaOx crystals present in the renal interstitium. These observations indicate a close relationship between inflammation and nephrolithiasis.

Clinical implications of physicochemistry of stone formation.

Measuring crystallization processes for assessing the risk of stone formation or the effect of treatment on that risk. In summary, crystallization processes are involved in the risk for stone formation at several levels. Several tests are available for assessing if crystalization is disturbed. It is important to first establish for which part of the urinary tract the information is sought and then adapt the experimental conditions to that site [53]. This information helps in visualizing what is happening inside the urinary tract of a SF and what the treatment measures prescribed may do to change that situation.

Academic development for urologists in the Kurdistan region of Iraq.

OBJECTIVES: Continuous education is mandatory for all urologists, and undertaking cooperative research is a very effective means for this. We describe the experience and possibilities for continuing education for urologists in the Kurdistan region of Iraq. We hope to provide a framework for stimulating urological education and research in other countries where urologists face the same obstacles. METHODS: Data were obtained from the perspective of two academics who co-operate with urologists from Iraq, and from the perspective of two officials from the Ministry of Higher education of the Kurdistan Regional Government who are responsible for stimulating continuous education. RESULTS: Based on a co-operative and supportive attitude of both Government and Academics, urologists in the Kurdistan region of Iraq have brought the standards of education and cooperative research to an internationally competitive level. CONCLUSION: The authors hope that the examples given here can stimulate urologists from Arab countries to fully engage in new urological developments, despite the obstacles that they perceive.

Metaphylaxis, diet and lifestyle in stone disease.

OBJECTIVE: The most common urinary stones (calcium salts, uric acid) form due to genetic factors and lifestyle. This review describes why, if and how medication and lifestyle changes can reduce the risk of formation. METHODS: Previous reports were reviewed to obtain information on three aspects of urolithiasis, i.e. epidemiology, mechanisms linking lifestyle and urolithiasis and lifestyle intervention for preventing urolithiasis. RESULTS: Epidemiological evidence links the prevalence of urinary stone formation to general lifestyle factors. Detailed analysis has identified individual lifestyle elements that affect the risk of urinary stone formation. Currently there are several concepts that explain the mechanism of stone formation. Urinary markers like calcium, oxalate, phosphate, uric acid and urinary pH are involved in all these concepts. Many studies show that changing (combinations of) specific lifestyle elements has a favourable effect on these urinary markers. Based on this evidence, protocols have been developed that use a combination of these lifestyle changes and medication to prevent stone formation. In well-controlled studies where patients are optimally informed and continuously motivated, these protocols clearly reduce the stone formation rate. In general practice the result is less clear, because the time and tools are insufficient to maintain long-term patient compliance in the use of medication and lifestyle advice. CONCLUSION: The risk of stone formation can be reduced in general practice when the patient's compliance is optimised by providing individualised advice, continuous information, and feedback and incorporation of the advice into a regular lifestyle. The use of 'e-tools' might enable this without increasing the time required from the physician.

In vivo measurement of bladder wall oxygen saturation using optical spectroscopy.

Current diagnosis, follow-up and treatment of patients suffering from bladder dysfunction are mainly symptom-targeted. A recently recognized cause of continuing bladder function loss is a deteriorated bladder microvasculature. Incorporating this aspect into the clinical diagnostic toolbox may improve treatment results. Recent developments in the field of optical spectroscopy now allow for non-invasive measurement of microvascular blood oxygen saturation in living tissue. We have recently reported pre-clinical data that show that this marker can be successfully measured in an animal bladder. In the animal model the marker differentiated bladders with loss of function from those with normal function. In the present paper, we report on the first in vivo measurement of this marker in the human bladder, as proof of principle, in the muscle of bladders with a normal function.

The detrusor glycogen content of a de-obstructed bladder reflects the functional history of that bladder during PBOO.

AIMS: To determine if detrusor glycogen content in a bladder after removal of a urethral obstruction reflects the situation of bladder dysfunction as it existed during the period of obstruction. METHODS: The glycogen content of the detrusor was scored using a Periodic Acid Schiff's (PAS) staining. It was related to the functional history of the bladder. Bladder tissue was obtained from a guinea-pig model for posterior urethral valves where animals had been obstructed for up to 10 weeks, de-obstructed and allowed to recover for 2--8 weeks. Bladder urodynamic function had been documented with multiple measurements for the complete period of obstruction and de-obstruction. RESULTS: The degree of glycogen deposition in a bladder after de-obstruction correlated directly with bladder function during obstruction. The strongest glycogen deposition was found in bladders having experienced the highest pressures, most instabilities, lowest compliance and highest contractility. In contrast, the bladder glycogen content was not related to the function of the bladder at the day the tissue was obtained, except for a relation between high glycogen content and continuing low compliance. CONCLUSIONS: The glycogen content of a bladder reflects the history of bladder dysfunction, also when measured during a recovery period. This window on the functional history of a bladder may be of clinical value for picking out potential bad-responders to therapy in patients with incomplete data on bladder function during a previous period of bladder obstruction.

Detrusor glycogen reflects the functional history of bladders with partial outlet obstruction.

OBJECTIVE: To assess the relationship between glycogen content in bladder detrusor tissue and historical bladder function in a guinea-pig model of partial bladder outlet obstruction (PBOO). MATERIALS AND METHODS: In male immature guinea pigs PBOO was created with a silver ring around the proximal urethra; a control group had a sham operation for comparison. Longitudinal individual urodynamic data were obtained weekly, so that guinea pigs were killed at different levels of bladder dysfunction. Bladder sections were stained with periodic acid-Schiff (PAS) to assess overall morphology and glycogen granule density, scored from 0 (no glycogen) to 3. Glycogen scores were related to both the end-stage and historical extremes of bladder function values. RESULTS: Glycogen granules were seen only in the detrusor; as their number increased their location expanded from only close to the serosa (glycogen score 1), through the detrusor (score 2) up to the urothelium (score 3). A glycogen score of 0 correlated with normal values for all urodynamic variables. Compared with a glycogen score of 0 a score of 1 correlated with significant (P < 0.05) changes in end-stage compliance (decrease) and contractility (increase) and significantly higher historical values for contractility, pressure and number of unstable contractions (NUC). In the group with a glycogen score of 2 there were significant changes in both the end-stage values and historical extremes for compliance, pressure, contractility and NUC (all P < 0.05). In the group with a glycogen score of 3 all these changes were even more dramatic, except for the end-stage contractility, for which the increase was not significant. From glycogen score 0 to score 3 all changes increased in magnitude. CONCLUSION: A high glycogen content reflects a history of abnormal urodynamic function. This finding exemplifies the added value of structural analysis to urodynamic studies. Further studies are needed to relate bladder structure to the potential for functional recovery.

The effect of oxybutynin on structural changes of the obstructed guinea pig bladder.

PURPOSE: Oxybutynin is used clinically to lower intravesical pressure and detrusor overactivity. In vitro it inhibits stretch induced bladder smooth muscle cell proliferation. We tested whether oxybutynin also prevents hypertrophic bladder changes in vivo in a model of partial bladder obstruction. MATERIALS AND METHODS: Subvesical obstruction was induced in immature guinea pigs by a silver ring around the urethra. Eight animals received 0.4 mg oxybutynin per kg body weight per day in 2 doses. Control groups were obstructed without oxybutynin treatment or sham operated. Urodynamic pressure flow studies were performed at 1-week intervals for 10 weeks in all animals under anesthesia with ketamine/xylazine. After 10 weeks the animals were sacrificed and the bladder was removed for structural analysis with periodic acid-Schiff stain, in which the number of glycogen granules was also scored as a measure of previous ischemia. RESULTS: Compared to the sham treated group obstructed animals had significantly higher intravesical pressure and detrusor overactivity, lower compliance and increased contractility. Obstructed animals that received oxybutynin retained normal intravesical pressure, detrusor overactivity and compliance. Their bladder contractility increased as in obstructed animals. The oxybutynin group showed less collagen infiltration in the detrusor and fewer glycogen granules compared to those in obstructed animals. CONCLUSIONS: Our results demonstrate that oxybutynin has a protective effect on bladder function and structure. Prevention of hypertrophic and ischemic bladder changes is an argument for an early start of oxybutynin treatment in children with inborn neurogenic bladder dysfunction, such as spina bifida, or in patients with urethral valves.

Tubular and interstitial nephrocalcinosis.

PURPOSE: We determined whether nephrocalcinosis is common and whether its detection is influenced by renal tissue processing. MATERIALS AND METHODS: Renal cortical and papillary tissue was obtained from the unaffected parts of 15 kidneys removed due to an oncological indication. The effect of tissue processing on the loss of crystals was studied in a kidney with nephrocalcinosis due to chronic pyelonephritis. Immediately frozen and formaldehyde fixed sections were analyzed by polarized light and Raman spectroscopy, and stained for calcium (Yasue) and hyaluronan. RESULTS: Although 13 of 15 snap-frozen sections from tumor kidneys contained birefringent particles (mean +/- SD 3.2 +/- 2.9 particles per cm(2)) in the renal tubules, this was not considered nephrocalcinosis because the crystals were not attached to the epithelial lining. Interstitial nephrocalcinosis was found on Yasue stain in 3 of 15 kidneys with tumor (20%). Calcium deposits were found in the papillary interstitium only, always together with hyaluronan. Formaldehyde fixed sections from the pyelonephritis kidney contained fewer renal tubular cell associated birefringent particles than immediately frozen sections (9.4 +/- 1.9 vs 41.6 +/- 1.2 per cm(2)). Particles were composed of calcium oxalate monohydrate (Yasue and Raman). CONCLUSIONS: There are 2 distinct forms of nephrocalcinosis, including tubular nephrocalcinosis, which seems to be reserved for specific conditions such as chronic pyelonephritis, and interstitial nephrocalcinosis. The incidence of tubular calcium oxalate nephrocalcinosis could be underestimated due to the loss of crystals during tissue processing for routine histology. The crystal binding molecule hyaluronan may have a role in the 2 forms of nephrocalcinosis.

Discrimination between nontumor bladder tissue and tumor by Raman spectroscopy.

We have applied Raman spectroscopy to discriminate between nontumor and tumor bladder tissue and to determine the biochemical differences therein. Tissue samples from 15 patients were collected, and frozen sections were made for Raman spectroscopy and histology. Twenty-five pseudocolor Raman maps were created in which each color represents a cluster of spectra measured on tissue areas of similar biochemical composition. For each cluster, the cluster-averaged spectrum (CAS) was calculated and classified as tumor and nontumor in accordance to pathohistology. Unguided hierarchical clustering was applied to display heterogeneity between and within groups of nontumor and tumor CAS. A linear discriminant analysis model was developed to discriminate between CAS from tumor and nontumor. The model was tested by a leave-one-patient-out validation, 84 of the 90 CAS (93%) were correctly classified with 94% sensitivity and 92% specificity. Biochemical differences between tumor and nontumor CAS areas were analyzed by fitting spectra of pure compounds to the CAS. Nontumor CAS showed higher collagen content while tumor CAS were characterized by higher lipid, nucleic acid, protein, and glycogen content. Raman spectroscopy enabled effective discrimination between tumor and nontumor bladder tissue based on characterized biochemical differences, despite heterogeneity expressed in both tumor and nontumor CAS.

Estrogen replacement increased the citrate and calcium excretion rates in postmenopausal women with recurrent urolithiasis.

PURPOSE: Epidemiological data indicate a sharp increase in urinary calcium stone formation after menopause. We investigated the role of menopausal estrogen replacement therapy on the urinary constituents and characteristics that may influence recurrent calcium oxalate stone disease. MATERIALS AND METHODS: Urinary constituents in 28 postmenopausal women on estrogen replacement therapy for more than 6 months were compared with those in 41 women who had never been exposed to estrogen after menopause. These 2 groups had a history of recurrent calcium oxalate urolithiasis. A group of age matched, nonstone forming volunteers who were and were not on estrogen served as controls. RESULTS: The 24-hour urine collection revealed significantly higher mean calcium plus or minus standard deviation (188.8 +/- 101.5 versus 129.2 +/- 80.9 mg./24 hours, p <0.01), citrate (576.6 +/- 237.9 versus 306.2 +/- 209.9 mg./24 hours, p <0.001) and agglomeration inhibition (203 +/- 106 versus 159 +/- 81 minutes, p <0.05) in stone forming women who were versus were not on estrogen. CONCLUSIONS: Higher urinary citrate and higher agglomeration inhibition in women exposed to estrogen may decrease the risk of subsequent calcium stone formation.