Longitudinal Trajectories of Estimated Glomerular Filtration Rate in a European Population of Living Kidney Donors.

A living donor (LD) kidney transplant is the best treatment for kidney failure, but LDs safety is paramount. We sought to evaluate our LDs cohort's longitudinal changes in estimated glomerular filtration rate (eGFR). We retrospectively studied 320 LDs submitted to nephrectomy between 1998 and 2020. The primary outcome was the eGFR change until 15 years (y) post-donation. Subgroup analysis considered distinct donor characteristics and kidney function reduction rate (%KFRR) post-donation [-(eGFR6 months(M)-eGFRpre-donation)/eGFRpre-donation*100]. Donors had a mean age of 47.3 ± 10.5 years, 71% female. Overall, LDs presented an average eGFR change 6 M onward of +0.35 mL/min/1.73 m2/year. The period with the highest increase was 6 M-2 Y, with a mean eGFR change of +0.85L/min/1.73 m2/year. Recovery plateaued at 10 years. Normal weight donors presented significantly better recovery of eGFR +0.59 mL/min/1.73 m2/year, compared to obese donors -0.18L/min/1.73 m2/year (p = 0.020). Noteworthy, these results only hold for the first 5 years. The subgroup with a lower KFRR (<26.2%) had a significantly higher decrease in eGFR overall of -0.21 mL/min/1.73 m2/year compared to the groups with higher KFRR (p < 0.001). These differences only hold for 6 M-2 Y. Moreover, an eGFR<50 mL/min/1.73 m2 was a rare event, with ≤5% prevalence in the 2-15 Y span, correlating with eGFR pre-donation. Our data show that eGFR recovery is significant and may last until 10 years post-donation. However, some subgroups presented more ominous kidney function trajectories.

Nephrectomy with Autotransplantation-A Key Treasure.

Background: Nephrectomy with autotransplantation (NAT) has been performed as an alternative treatment for complex renovascular lesions, intricate ureteral strictures and nephron-sparing surgery in complex renal tumors. Methods: A retrospective observational study was conducted including patients who underwent a NAT from January 2010 to September 2023. Data collected included surgery indications, surgical technique, complications according to Clavien-Dindo classification and mean hospital stay. Descriptive and inferential statistical analysis was performed using IBM® SPSS® Statistics version 28.0.1.0. Results: A total of 34 consecutive patients underwent 38 NATs at our institution. Surgery indications were complex renovascular conditions in 35 cases (92.1%), of which 24 had renal artery aneurysms, and ureteral injuries in 3 cases (7.9%). Thirty-four kidneys (89.5%) were retrieved through a laparoscopic approach. No significant difference was observed between post- and pre-operative creatinine levels (0.81 vs. 0.72, p = 0.303). Early high-grade complications developed in 12 procedures (31.6%). Median cold ischemia time was significantly longer in patients who developed complications (163.0 vs. 115.0, p = 0.010). The median hospital stay was 10 days (8-13). The median follow-up was 51.5 months. Conclusions: NAT emerges as a successful therapeutic strategy for a highly select group of patients dealing with intricate ureteral lesions and kidney vascular abnormalities, demonstrating positive outcomes that endure in the long term.

Transperitoneal vs. Retroperitoneal Approach in Laparoscopic Partial Nephrectomy for Posterior Renal Tumors: A Retrospective, Multi-Center, Comparative Study.

Purpose: The aim of our study is to compare the perioperative, functional, and oncological outcomes of laparoscopic transperitoneal partial nephrectomy (LTPN) and laparoscopic retroperitoneal partial nephrectomy (LRPN) for posterior cT1 renal tumors. Methods: We retrospectively collected data on all patients who consecutively underwent LTPN and LRPN for posterior cT1 renal tumors in three different centers from January 2015 to January 2023. Patients with a single, unilateral, cT1 renal mass, located in the posterior renal surface were included. Patients' data regarding perioperative, functional, and oncological outcomes were collected from medical records and statistically analyzed and compared. Results: A total of 128 patients was obtained, with 53 patients in the LPTN group and 75 patients in the LRPN group. Baseline characteristics were similar. Warm ischemia time (WIT) (18.8 vs. 22.6 min, p = 0.002) and immediate postoperative eGFR drop (-6.1 vs. -13.0 mL/min/1.73 m2, p = 0.047) were significantly lower in the LPTN group. Estimated blood loss (EBL) (100 vs. 150 mL, p = 0.043) was significantly lower in the LRPN group. All other perioperative and functional outcomes and complications were similar between the groups. The positive surgical margin (PSM) rate was lower in the LRPN group, although without statistical significance (7.2% vs. 13.5%, p = 0.258). Surgical success defined by Trifecta (WIT ≤ 25 min, no PSM, and no major postoperative complication) was similar between both approaches. Conclusions: LTPN has significantly shorter WIT and a significantly smaller drop in immediate eGFR when compared to LRPN for posterior renal tumors. On the other hand, LRPN has significantly less EBL than LTPN. LRPN demonstrated fewer PSMs than LTPN, albeit without statistical significance. In terms of overall surgical success, as defined by Trifecta, both approaches achieved similar results.

Outcomes of Urinary Tract Endometriosis-Laparoscopic Treatment: A 10-Year Retrospective Study.

INTRODUCTION: Urinary tract endometriosis (UTE), a rare manifestation, encompasses bladder and ureteral involvement. Surgical intervention is commonly recommended for UTE, though the optimal surgical approach remains a subject of debate. This study aims to report our centre's experience with UTE. METHODS: We conducted a retrospective cohort study of 55 patients who underwent surgical treatment for UTE at a single tertiary centre over a 10-year period (2012-2022). Patient data, including demographics, symptoms, intraoperative findings, and complications, were collected from medical records. Data were statistically analysed, and correlations were explored. RESULTS: The study population had a mean age of 37.11 years, with dysmenorrhea (89.1%) being the most common symptom. Bladder endometriosis was present in 27 cases, ureteral endometriosis in 25, and mixed-location in 3. Laparoscopy was the primary surgical approach, with multidisciplinary teams involving urologists. There were six patients with postoperative complications, and there were six (10.9%) recurrences of endometriosis. A positive correlation was found between age and recurrence, but no significant predictors of recurrence were identified in our analysis. CONCLUSIONS: Laparoscopic treatment of urinary endometriosis is safe and effective. Multidisciplinary collaboration plays a pivotal role in addressing this challenging condition.

Metastatic hidradenocarcinoma: a report of two rare cases.

BACKGROUND: Hidradenocarcinoma is a rare malignant sweat gland tumour, characterized by a slow but aggressive course, with high rates of local recurrence and metastasis. Due to its rarity, histological criteria and therapeutic guidelines are poorly defined, posing a major challenge for clinicians and pathologists. OBJECTIVES: To present two new cases of metastatic hidradenocarcinoma as well as a review of the literature. MATERIALS & METHODS: We describe two case studies and a review of the literature based on a search using the MEDLINE (PubMed) electronic database. RESULTS: The first patient was a 61-year-old woman with a perimamillary hidradenocarcinoma that arose from the malignant transformation of a benign childhood lesion and developed regional lymph node metastases after wide excision and adjuvant radiotherapy. The second patient was a 63-year-old man who developed cutaneous and renal metastases several years after the complete excision of a lumbar hidradenocarcinoma. As far as we can ascertain, kidney metastasis from hidradenocarcinoma has not previously been described. CONCLUSION: Most authors recommend wide excision as the treatment of choice for hidradenocarcinoma, however, optimal adjuvant therapy remains to be determined. Our cases add to the limited knowledge available, but high-quality studies to find new effective treatments are needed.

Renal Artery Thrombosis After Laparoscopic Living-Donor Nephrectomy: A Case Report.

Renal transplantation is the most successful treatment for end-stage renal disease, and the number of living-donor nephrectomies has been rising over the years due to the advantages it offers over deceased donors. Although this surgery is considered safe, it can be associated with complications amplified by the fact that it is performed on a healthy individual. Renal artery thrombosis is a rare disease that needs prompt diagnosis and treatment to avoid renal function deterioration, which becomes even more important in cases of solitary kidneys. We report the first case of renal artery thrombosis after laparoscopic living-donor nephrectomy treated with catheter-directed thrombolysis.

Association of the Calcification Score of the Abdominal Aorta, Common Iliac, and Renal Arteries with Outcomes in Living Kidney Donors.

BACKGROUND: Vascular calcification is an ever-more-common finding in protocoled pre-transplant imaging in living kidney donors. We intended to explore whether a connection could be found between the Agatston calcification score, prior to kidney donation, and post-donation renal function. METHODS: This is a retrospective analysis of 156 living kidney donors who underwent living donor nephrectomy between January 2010 and December 2016. We quantified the total calcification score (TCaScore) by calculating the Agatston score for each vessel, abdominal aorta, common iliac, and renal arteries. Donors were placed into two different groups based on their TCaScore: <100 TCaScore group and ≥100 TCaScore group. The relationship between TCaScore, 1-year eGFR, proteinuria, and risk of 1 measurement of decreased renal function (eGFR < 60 mL/min/1.73 m2) over 5 years of follow-up was investigated. RESULTS: The ≥100 TCaScore group consisted of 29 (19%) donors, with a median (interquartile range) calcification score of 164 (117-358). This group was significantly older, 56.7 ± 6.9 vs. 45.5 ± 10.6 (p < 0.001), had a higher average BMI (p < 0.019), and had a lower preoperative eGFR (p < 0.014). The 1-year eGFR was similarly diminished, 69.9 ± 15.7 vs. 76.3 ± 15.5 (p < 0.048), while also having an increased risk of decreased renal function during the follow-up, 22% vs. 48% (p < 0.007). CONCLUSIONS: Our study, through univariate analyses, found a relationship between a TCaScore > 100, lower 1-year eGFR, and decreased renal function in 5 years. However, a higher-than-expected vascular calcification should not be an excluding factor in donors, although they may require closer monitoring during follow-up.

Age-related white matter hyperintensities and overactive bladder: A systematic review.

INTRODUCTION: Age-related white matter hyperintensities (ARWMHs) on brain magnetic resonance imaging have been associated with lower urinary tract symptoms/dysfunction (LUTS/LUTD), namely overactive bladder (OAB) and detrusor overactivity. We aimed to systematically review existing data on the association between ARWMH and LUTS and which clinical tools have been used for this assessment. MATERIALS AND METHODS: We searched PubMed/MEDLINE, Cochrane Library, and clinicaltrials.gov (from 1980 to November 2021) and considered original studies reporting data on ARWMH and LUTS/LUTD in patients of both sexes aged 50 or above. The primary outcome was OAB. We calculated the unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the outcomes of interest using random-effects models. RESULTS: Fourteen studies were included. LUTS assessment was heterogeneous and mainly based on the use of nonvalidated questionnaires. Urodynamics assessment was reported in five studies. ARWMHs were graded using visual scales in eight studies. Patients with moderate-to-severe ARWMHs were more likely to present with OAB and urgency urinary incontinence (UUI; OR = 1.61; 95% CI: 1.05-2.49, p = 0.03), I2 = 21.3%) when compared to patients with similar age and absent or mild ARWMH. DISCUSSION AND CONCLUSIONS: High-quality data on the association between ARWMH and OAB is scarce. Patients with moderate to severe ARWMH showed higher levels of OAB symptoms, including UUI, when compared to patients with absent or mild ARWMH. The use of standardized tools to assess both ARWMH and OAB in these patients should be encouraged in future research.

Renal cell carcinoma in native kidneys before transplantation - When will we stop waiting?

INTRODUCTION: Kidney transplantation requires immunosuppression, traditionally regarded as a risk factor for progression in all malignancies. Based on the Cincinnati Registry, a waiting period before transplantation is therefore mandatory. However, recent evidence suggests this increased risk is restricted to particular tumors, whereas others like renal cell carcinoma (RCC) are not negatively affected. We aimed to compare oncological outcomes of RCC in native kidneys of end-stage renal disease (ESRD) patients, according to their transplantation or dialysis status. MATERIAL AND METHODS: Retrospective analysis of all ESRD patients diagnosed with RCC between 2010 and 2020 in our center. Recurrence-free survival (RFS) and overall survival (OS) were estimated with Kaplan-Meier curves. Multivariable Cox regression model was used to evaluate their association with kidney transplantation. RESULTS: Clinical and pathological characteristics were similar between groups. Kidney transplant recipients had similar risk of recurrence (hazard ratio [HR] 0.40, 95% confidence interval [CI) 0.04-4.46, p = 0.458) and overall survival (HR 0.34, 95%CI 0.07-1.77, p = 0.202) as dialyzed patients. On multivariable Cox regression model, presence or absence of transplantation was not significantly associated with RFS (p = 0.479) or OS (p = 0.236). Time on dialysis was the only independent predictor of worse survival (HR 1.86, 95%CI 1.18-2.93, p = 0.008). CONCLUSIONS: Most RCC in native kidneys of ESRD patients are low-grade, low-stage and exhibit favourable pathological and outcome features. Immunosuppression does not seem to have an impact on oncological outcomes, but an increased time on dialysis seems to be associated with worse overall survival. Therefore, waiting time for transplantation for these tumors could be reduced.

Sapheno-Cavernous Shunt: A Vascular Approach In The Treatment Of Ischemic Priapism.

Priapism is an urologic emergency defined as an erection that persists for more than 4 hours and is unrelated or lasts beyond sexual stimulation. Ischemic priapism, caused by prolonged venous occlusion within the corporal bodies, works as a compartment syndrome that requires prompt resolution in order to preserve erectile function. We present two cases of ischemic priapism refractory to conventional treatment that were treated with the help of vascular surgeons. In both cases a sapheno-cavernous shunt was effective in achieving detumescence and erectile function recovery. Despite rarely described in literature, this can be a safe and effective technique in the treatment of ischemic priapism.

Perioperative and oncological outcomes of laparoscopic and open radical nephroureterectomy for locally advanced upper tract urothelial carcinoma: a single-center cohort study.

Introduction: Open radical nephroureterectomy (ONU) is the standard of care for treatment of upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LNU) is increasingly being used due to better perioperative outcomes. However, its oncological safety remains controversial, in particular for advanced disease.We aimed to compare perioperative and oncological outcomes between surgical approaches in locally advanced UTUC (≥pT3 and/or pN+). Material and methods: This study was a retrospective analysis of all 48 patients submitted to radical nephroureterectomy for advanced UTUC between 2006 and 2020 in our center.Perioperative data were compared between groups. Bladder tumor-free survival (BTFS), metastasis-free survival (MFS) and cancer-specific survival (CSS) were estimated using Kaplan-Meier curves and compared with log-rank p test. Multivariable Cox regression model was used to evaluate their association with surgical approach. Results: Clinical and pathological characteristics were similar between groups. LNU had lower blood loss (p = 0.031), need for transfusion (p = 0.013) and length of hospital stay (p <0.001), with similar operative time (p = 0.860).LNU was associated with better MFS (hazard ratio [HR]: 0.43, 95% confidence interval [CI] 0.20-0.93, p = 0.033) and CSS (HR: 0.42, 95%CI 0.19-0.94, p = 0.036). Median time to cancer death was 41 months for LNU and 12 months for ONU (log-rank p = 0.029). BTFS was similar between groups (HR: 0.60, 95%CI 0.17-2.11, p = 0.427). On multivariable Cox regression model, surgical approach wasn't significantly associated with MFS (p = 0.202), CSS (p = 0.149) or BTFS (p = 0.586). Conclusions: In our cohort of advanced UTUC, LNU did not result in inferior oncological control compared to ONU. The minimally invasive approach conferred an advantage in perioperative outcomes.

Hereditary Leiomyomatosis and Renal Cell Cancer-Recognizing Patterns May Save Lives.

In 2001, Finish investigators described a rare familiar syndrome characterized by an inherited susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). Hereditary leiomyomatosis and renal cell cancer (HLRCC) is now linked to a germline mutation in the fumarate hydratase (FH) gene that encodes a Krebs cycle enzyme, transforming fumarate to malate. The accumulation of fumarate, an oncometabolite, promotes tumorigenesis. We present a case of a 41-year-old female diagnosed with HLRCC after a radical nephrectomy due to renal cell cancer. Genetic analyses confirmed a novel FH mutation. Close follow-up allowed for a precocious diagnosis of a metachronous renal tumor and later a hepatic metastasis. Her family was also counseled and offered genetic testing. As observed in this case, the diagnosis of HLRCC is of paramount importance for patients and their families: there is a 15% cumulative lifetime risk of developing RCC, which frequently occurs in young patients and metastasizes at an early stage. Implementing a regular follow-up with adequate imaging examinations may help save lives.

Lower donated kidney volume is associated with increased risk of lower graft function and acute rejection at 1 year after living donor kidney-a retrospective study.

Kidney volume has been proven to be a surrogate marker of nephron mass and renal function. We studied 190 donor and recipient pairs undergoing living donor kidney transplantation at our institution during 9 years. Different metrics of donor kidney volume (DKV) were explored: alone or indexed to recipient's anthropometry, as body surface area (BSA). DKV/BSA (min. 49.7; P33rd 77.7; P67th 95.3; max. 176 cm3 /m2 ) was chosen given its higher correlation with eGFR at 1 year, and recipients were divided according to its tertiles (T). The eGFR at 1 year was lower in T1, when compared with T2 (P = 0.015) and T3 (P < 0.001). In a multivariable model, a regression spline revealed that a DKV/BSA lower than 80 was significantly associated with an eGFR at 1 year <60. In the first 6 years, the overall annual eGFR slope was -0.90 ml/min/year. Acute rejection occurred in 19%, 11%, and 0% of patients in T1, T2, and T3, respectively (P < 0.001). DKV/BSA increased stepwise from cellular- (n = 12) to antibody-mediated (n = 7) AR cases and to those without AR (n = 171; P = 0.002; no AR versus cellular AR). Lower DKV/BSA ratio was associated with significantly worse graft function and higher incidence of AR. Hence, it can be a tool for better selection of donors in order to improve graft outcomes, particularly in the setting of multiple potential living donors or kidney paired exchange programs.

Remaining kidney volume indexed to weight as a strong predictor of estimated glomerular filtration rate at 1 year and mid-term renal function after living-donor nephrectomy - a retrospective observational study.

The donors' estimated glomerular filtration rate (eGFR) after living nephrectomy has been a concern, particularly in donors with smaller kindeys. Therefore, we developed this retrospective observational study in 195 donors to determine the ability remaining kidney volume indexed to weight (RKV/W) to predict eGFR at 1 year through multivariate linear regression and to explore this relationship between annual eGFR change from 1 to 4 years postdonation evaluated by a linear mixed model. Comparing RKV/W tertiles (T1, T2, T3), RKV/W was a good predictor of 1-year eGFR which was significantly better in T3 donors. Gender, predonation eGFR, and RKV/W were independent predictors of eGFR at 1-year. In a subgroup with predonation eGFR < 90mL/min/1.73 m2 , a significant prediction of eGFR < 60mL/min/1.73 m2 was detected in males with RKV/W ≤ 2.51cm3 /kg. Annual eGFR (ml/min/year) change from 1 to 4 years was + 0.77. RKV/W divided by tertiles (T1-T3) was the only significant predictor: T2 and T3 donors had an annual eGFR improvement opposing to T1. RKV/W was a good predictor of eGFR at 1 year, independently from predonation eGFR. A higher RKV/W was associated with improved eGFR at 1 year. A decline in eGFR on the four years after surgery was only noticeable in donors with RKV/W ≤ 2.13cm3 /kg.

ß3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release.

BACKGROUND AND PURPOSE: The mechanism by which ß3 receptor agonists (e.g. mirabegron) control bladder overactivity may involve adenosine release from human and rat detrusor smooth muscle. Retrograde activation of adenosine A1 receptors reduces ACh release from cholinergic bladder nerves. ß3 -Adrenoceptors usually couple to adenylyl cyclase. Here we investigated, which of the cAMP targets, protein kinase A or the exchange protein directly activated by cAMP (EPAC) could be involved in this cholinergic inhibition of the bladder. EXPERIMENTAL APPROACH: [3 H]ACh and adenosine release from urothelium-denuded detrusor strips of cadaveric human organ donors and rats were measured by liquid scintillation spectrometry and HPLC, respectively. In vivo cystometry was also performed in urethane-anaesthetized rats. KEY RESULTS: The exchange protein directly activated by cAMP (EPAC) inhibitor, ESI-09, prevented mirabegron- and isoprenaline-induced adenosine release from human and rat detrusor strips respectively. ESI-09, but not the PKA inhibitor, H-89, attenuated inhibition of [3 H]ACh release from stimulated (10 Hz) detrusor strips caused by activating ß3 -adrenoceptors, AC (forskolin) and EPAC1 (8-CTP-2Me-cAMP). Isoprenaline-induced inhibition of [3 H]ACh release was also prevented by inhibitors of PKC (chelerythrine and Go6976) and of the equilibrative nucleoside transporter 1 (ENT1; dipyridamole and NBTI), but not by PLC inhibition with U73122. Pretreatment with ESI-09, but not with H-89, prevented the reduction of the voiding frequency caused by isoprenaline and forskolin in vivo. CONCLUSION AND IMPLICATIONS: Data suggest that ß3 -adrenoceptor-induced inhibition of cholinergic neurotransmission in human and rat urinary bladders involves activation of an EPAC1/PKC pathway downstream cAMP production resulting in adenosine outflow via ENT1.

Mini-incision Living Donor Nephrectomy and Trans-peritoneal Laparoscopic Nephrectomy: Will There Be a Place for New Evidence?

OBJECTIVES: To compare mini-incision donor nephrectomy (MDN) with laparoscopic donor nephrectomy (LDN) performed by the same surgical team, regarding short- and long-term outcomes. METHODS: Three hundred and five patients, who underwent donor nephrectomy in our institution, through an MDN (n = 141) between January 1998-November 2011 and LDN (n = 164) since June 2010-December 2017, were compared. RESULTS: The mean operative time for MDN (120 ± 29 minutes) was not significantly different when compared to LDN (113 ± 34 minutes), but when comparing the first 50 LDN and the 50 most recent, we found a reduction in the duration of the procedure. Laparoscopic donors had a shorter warm ischemia time (229 seconds vs 310 seconds, P = .01), particularly the 50 most recent, hospital stay (4.3 days vs 5.9 days, P < .001), and postoperative complications (P = .03). The incidence of graft acute tubular necrosis (ATN) was superior in the MDN (89% vs 25%, P < .001), although there was no significant difference regarding first-year serum creatinine (SCr) and glomerular filtration rate (GFR) (SCr 1.38 mg/dL vs SCr 1.33 mg/dL and GFR 63.7 mL/min vs 63.1 mL/min) comparing the 2 groups. Long-term graft survival did not significantly differ between groups. There was also no relationship between postoperative ATN events and long-term graft function. CONCLUSIONS: With the growing experience of the high-volume centers and with specialized teams, LDN could be considered the most suitable technique for living donor nephrectomy with better results in short-term results (warm ischemia time, hospital stay, and postoperative complications), without difference in long-term outcomes.

Inhibition of cholinergic neurotransmission by ß3-adrenoceptors depends on adenosine release and A1-receptor activation in human and rat urinary bladders.

The direct detrusor relaxant effect of ß3-adrenoceptor agonists as a primary mechanism to improve overactive bladder symptoms has been questioned. Among other targets, activation of ß3-adrenoceptors downmodulate nerve-evoked acetylcholine (ACh) release, but there is insufficient evidence for the presence of these receptors on bladder cholinergic nerve terminals. Our hypothesis is that adenosine formed from the catabolism of cyclic AMP in the detrusor may act as a retrograde messenger via prejunctional A1 receptors to explain inhibition of cholinergic activity by ß3-adrenoceptors. Isoprenaline (1 µM) decreased [3H]ACh release from stimulated (10 Hz, 200 pulses) human (-47 ± 5%) and rat (-38 ± 1%) detrusor strips. Mirabegron (0.1 µM, -53 ± 8%) and CL316,243 (1 µM, -37 ± 7%) mimicked isoprenaline (1 µM) inhibition, and their effects were prevented by blocking ß3-adrenoceptors with L748,337 (30 nM) and SR59230A (100 nM), respectively, in human and rat detrusor. Mirabegron and isoprenaline increased extracellular adenosine in the detrusor. Blockage of A1 receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 100 nM) or the equilibrative nucleoside transporters (ENT) with dipyridamole (0.5 µM) prevented mirabegron and isoprenaline inhibitory effects. Dipyridamole prevented isoprenaline-induced adenosine outflow from the rat detrusor, and this effect was mimicked by the ENT1 inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI, 30 µM). Cystometry recordings in anesthetized rats demonstrated that SR59230A, DPCPX, dipyridamole, and NBTI reversed the decrease in the voiding frequency caused by isoprenaline (0.1-1,000 nM). Data suggest that inhibition of cholinergic neurotransmission by ß3-adrenoceptors results from adenosine release via equilibrative nucleoside transporters and prejunctional A1-receptor stimulation in human and rat urinary bladder.

Increased Urinary Adenosine Triphosphate in Patients With Bladder Outlet Obstruction Due to Benign Prostate Hyperplasia.

BACKGROUND: Diagnosis of bladder outflow obstruction (BOO) in patients with lower urinary tract (LUT) symptoms is challenging without using invasive urodynamic tests. Recently, we showed in vitro that urothelial strips from patients with benign prostatic hyperplasia (BPH) release more ATP than controls. Here, we tested whether urinary ATP can be used as a wall tension transducer non-invasive biomarker to detect BOO in patients with BPH. METHODS: 79 male patients with BOO and 22 asymptomatic controls were recruited prospectively. Patients were asked to complete the International Prostate Symptom Score (IPSS) questionnaire and to void at normal desire into a urinary flowmeter; the postvoid residual volume was determined by suprapubic ultrasonography. Urine samples from all individuals were examined for ATP, creatinine, and lactate dehydrogenase. RESULTS: BOO patients had significantly higher (P < 0.001) urinary ATP normalized by the voided volume (456 ± 36 nmol) than age-matched controls (209 ± 35 nmol). Urinary ATP amounts increased with the voided volume, but the slope of this rise was higher in BOO patients than in controls. A negative correlation was detected between urinary ATP and flow rate parameters, namely maximal flow rate (r = -0.310, P = 0.005), Siroky flow-volume normalization (r = -0.324, P = 0.004), and volume-normalized flow rate index (r = -0.320, P = 0.012). We found no correlation with LUT symptoms IPSS score. Areas under the receiver operator characteristics (ROC) curves were 0.91 (95%CI 0.86-0.96, P < 0.001) for ATP alone and 0.88 (95%CI 0.81-0.94, P < 0,001) when adjusted to urinary creatinine. CONCLUSIONS: Patients with BOO release higher amounts of ATP into the urine than the control group. The high area under the ROC curve suggests that urinary ATP can be a high-sensitive non-invasive biomarker of BOO, which may have a discriminative value of detrusor competence when comparing BPH patients with low urinary flow rates. Prostate 76:1353-1363, 2016. © 2016 Wiley Periodicals, Inc.

Activation of P2Y6 Receptors Facilitates Nonneuronal Adenosine Triphosphate and Acetylcholine Release from Urothelium with the Lamina Propria of Men with Bladder Outlet Obstruction.

PURPOSE: Deregulation of purinergic bladder signaling may contribute to persistent detrusor overactivity in patients with bladder outlet obstruction. Activation of uridine diphosphate sensitive P2Y6 receptors increases voiding frequency in rats indirectly by releasing adenosine triphosphate from the urothelium. To our knowledge this mechanism has never been tested in the human bladder. MATERIALS AND METHODS: We examined the role of the uridine diphosphate sensitive P2Y6 receptor on tetrodotoxin insensitive nonneuronal adenosine triphosphate and [(3)H]acetylcholine release from the human urothelium with the lamina propria of control organ donors and patients with benign prostatic hyperplasia. RESULTS: The adenosine triphosphate-to-[(3)H]acetylcholine ratio was fivefold higher in mucosal urothelium/lamina propria strips from benign prostatic hyperplasia patients than control men. The selective P2Y6 receptor agonist PSB0474 (100 nM) augmented by a similar amount adenosine triphosphate and [(3)H]acetylcholine release from mucosal urothelium/lamina propria strips from both groups of individuals. The facilitatory effect of PSB0474 was prevented by MRS2578 (50 nM) and by carbenoxolone (10 µM), which block P2Y6 receptor and pannexin-1 hemichannels, respectively. Blockade of P2X3 (and/or P2X2/3) receptors with A317491 (100 nM) also attenuated release facilitation by PSB0474 in control men but not in patients with benign prostatic hyperplasia. Immunolocalization studies showed that P2Y6, P2X2 and P2X3 receptors were present in choline acetyltransferase positive urothelial cells. In contrast to P2Y6 staining, choline acetyltransferase, P2X2 and P2X3 immunoreactivity decreased in the urothelium of benign prostatic hyperplasia patients. CONCLUSIONS: Activation of P2Y6 receptor amplifies mucosal adenosine triphosphate release underlying bladder overactivity in patients with benign prostatic hyperplasia. Therefore, we propose selective P2Y6 receptor blockade as a novel therapeutic strategy to control persistent storage symptoms in obstructed patients.