RANKL is a mediator of bone resorption in idiopathic hypercalciuria

Background and objectives: This study aimed to determine the expression of osteoprotegerin, receptor activator of nuclear factor kappa B ligand, interleukin-la, transforming growth factor-beta, and basic fibroblast growth factor in stone-forming patients with idiopathic hypercalciuria. Design, setting, participants, & measurements: Immunohistochemical analysis was performed in undecalcified bone samples previously obtained from 36 transiliac bone biopsies of patients who had idiopathic hypercalciuria and whose histomorphometry had shown lower bone volume, increased bone resorption, and prolonged mineralization lag time. Results: Bone expression of receptor activator of nuclear factor kappa B ligand and osteoprotegerin was significantly higher in patients with idiopathic hypercalciuria versus control subjects. Transforming growth factor-beta immunostaining was lower in patients with idiopathic hypercalciuria than in control subjects and correlated directly with mineralization surface. Interleukin-la and basic fibroblast growth factor staining did not differ between groups. Receptor activator of nuclear factor kappa B ligand bone expression was significantly higher in patients who had idiopathic hypercalciuria and exhibited higher versus normal bone resorption. Conclusion: A higher expression of receptor activator of nuclear factor kappa B ligand in bone tissue suggests that increased bone resorption in patients with idiopathic hypercalciuria is mediated by receptor activator of nuclear factor kappa B ligand. Osteoprotegerin bone expression might have been secondarily increased in an attempt to counteract the actions of receptor activator of nuclear factor kappa B ligand. The low bone expression of transforming growth factor-beta could contribute to the delayed mineralization found in such patients.

AT(1) blockade during lactation as a model of chronic nephropathy: mechanisms of renal injury

Suppression of the renin-angiotensin system during lactation causes irreversible renal structural changes. In this study we investigated 1) the time course and the mechanisms underlying the chronic kidney disease caused by administration of the AT(1) receptor blocker losartan during lactation, and 2) whether this untoward effect can be used to engender a new model of chronic kidney disease. Male Munich-Wistar pups were divided into two groups: C, whose mothers were untreated, and L(Lact), whose mothers received oral losartan (250 mg.kg(-1).day(-1)) during the first 20 days after delivery. At 3 mo of life, both nephron number and the glomerular filtration rate were reduced in L(Lact) rats, whereas glomerular pressure was elevated. Unselective proteinuria and decreased expression of the zonula occludens-1 protein were also observed, along with modest glomerulosclerosis, significant interstitial expansion and inflammation, and wide glomerular volume variation, with a stable subpopulation of exceedingly small glomeruli. In addition, the urine osmolality was persistently lower in L(Lact) rats. At 10 mo of age, L(Lact) rats exhibited systemic hypertension, heavy albuminuria, substantial glomerulosclerosis, severe renal interstitial expansion and inflammation, and creatinine retention. Conclusions are that 1) oral losartan during lactation can be used as a simple and easily reproducible model of chronic kidney disease in adult life, associated with low mortality and no arterial hypertension until advanced stages; and 2) the mechanisms involved in the progression of renal injury in this model include glomerular hypertension, glomerular hypertrophy, podocyte injury, and interstitial inflammation.

Fluoxetine effect on kidney water reabsorption

Background. The pathogenesis of hyponatraemia caused by fluoxetine (Fx) use in the treatment of depression is not well understood. It has been attributed to a SIADH, although ADH-enhanced plasma level has not yet been demonstrated in all the cases reported in humans. This experiment aimed at investigating the effect of fluoxetine on the kidney and more specifically in the inner medullary collecting duct (IMCD). Methods. ( 1) In vivo study: ( a) 10 rats were injected daily i. p. with 10 mg/kg fluoxetine doses. After 10 days, rats were sacrificed and blood and kidneys were collected. (b) Immunoblotting studies for AQP2 protein expression in the IMCD from injected rats and in IMCD tubules suspension from 10 normal rats incubated with 10(-7) M fluoxetine. ( 2) In vitro microperfusion study: The osmotic water permeability (P-f, mu m/s) was determined in normal rats IMCD (n = 6), isolated and perfused by the standard methods. Results. In vivo study: ( a) Injected rats with fluoxetine lost about 12% body weight; Na+ plasma level decreased from 139.3 +/- 0.78 mEq/1 to 134.9 +/- 0.5 mEq/1 ( p < 0.01) and K+ and ADH plasma levels remained unchanged. ( b) Immunoblotting densitometric analysis of the assays showed an increase in AQP2 protein abundance of about 40%, both in IMCDs from injected rats [ control period (cont) 99.6 +/- 5.2 versus Fx 145.6 +/- 16.9, p < 0.05] and in tubule suspension incubated with fluoxetine ( cont 100.0 +/- 3.5 versus 143.0 +/- 2.0, p < 0.01). In vitro microperfusion study fluoxetine increased Pf in the IMCD in the absence of ADH from the cont 7.24 +/- 2.07 to Fx 15.77 +/- 3.25 ( p < 0.01). Conclusion. After fluoxetine use, the weight and plasma Na+ level decreased, and the K+ and ADH plasma levels remained unchanged, whereas the AQP2 protein abundance and water absorption in the IMCD increased, leading us to conclude that the direct effect of fluoxetine in the IMCD could explain at least in part, the hyponatraemia found sometime after this drug use in humans.

K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients

The guidelines proposed by the Kidney Disease Outcomes Quality Initiative (K/DOQI) suggested that intact parathyroid hormone (iPTH) should be maintained in a target range between 150 and 300 pg ml(-1) for patients with stage 5 chronic kidney disease. Our study sought to verify the effectiveness of that range in preventing bone remodeling problems in hemodialysis patients. We measured serum ionized calcium and phosphorus while iPTH was measured by a second-generation assay. Transiliac bone biopsies were performed at the onset of the study and after completing 1 year follow-up. The PTH levels decreased within the target range in about one-fourth of the patients at baseline and at the end of the study. The bone biopsies of two-thirds of the patients were classified as showing low turnover and a one-fourth showed high turnover, the remainder having normal turnover. In the group achieving the target levels of iPTH 88% had low turnover. Intact PTH levels less than 150 pg ml(-1) for identifying low turnover and greater than 300 pg ml(-1) for high turnover presented a positive predictive value of 83 and 62%, respectively. Our study suggests that the iPTH target recommended by the K/DOQI guidelines was associated with a high incidence of low-turnover bone disease, suggesting that other biochemical markers may be required to accurately measure bone-remodeling status in hemodialysis patients.

Impact of mild acute kidney injury (AKI) on outcome after open repair of aortic aneurysms

Recently, mild AKI has been considered as a risk factor for mortality in different scenarios. We conducted a retrospective analysis of the risk factors for two distinct definitions of AKI after elective repair of aortic aneurysms. Logistic regression was carried out to identify independent risk factors for AKI ( defined as >= 25% or >= 50% increase in baseline SCr within 48 h after surgery, AKI 25% and AKI 50%, respectively) and for mortality. Of 77 patients studied ( mean age 68 +/- 10, 83% male), 57% developed AKI 25% and 33.7% AKI 50%. There were no differences between AKI and control groups regarding comorbidities and diameter of aneurysms. However, AKI patients needed a supra-renal aortic cross-clamping more frequently and were more severely ill. Overall in-hospital mortality was 27.3%, which was markedly higher in those requiring a supra-renal aortic cross-clamping. The risk factors for AKI 25% were suprarenal aortic cross-clamping ( odds ratio 5.51, 95% CI 1.05-36.12, p = 0.04) and duration of operation for AKI 25% ( OR 6.67, 95% CI 2.23-19.9, p < 0.001). For AKI 50%, in addition to those factors, post-operative use of vasoactive drugs remained as an independent factor ( OR 6.13, 95% CI 1.64-22.8, p = 0.005). The risk factors associated with mortality were need of supra-renal aortic cross-clamping ( OR 9.6, 95% CI 1.37-67.88, p = 0.02), development of AKI 50% ( OR 8.84, 95% CI 1.31-59.39, p = 0.02), baseline GFR lower than 49 mL/min ( OR 17.07, 95% CI 2.00 145.23, p = 0.009), and serum glucose > 118 mg/dL in the post-operative period ( OR 19.99, 95% CI 2.32-172.28, p = 0.006). An increase of at least 50% in baseline SCr is a common event after surgical repair of aortic aneurysms, particularly when a supra-renal aortic cross-clamping is needed. Along with baseline moderate chronic renal failure, AKI is an independent factor contributing to the high mortality found in this scenario.

Trigonal injection of botulinum toxin-A does not cause vesicoureteral reflux in neurogenic patients

Aims: We evaluated the effect of botulinum toxin type A (BTX-A) injections in the trigone on the antireflux mechanism and evaluated its short-term efficacy. Materials and Methods: Between April and December 2006, 21 patients (10 men and 11 women) were prospectively evaluated. All were incontinent due to refractory NDO and underwent detrusor injection of 300 units of BTX-A, including 50 units into the trigone. Baseline and postoperative evaluation after eight weeks included cystogram, urinary tract ultrasound and urodynamics. Results: At baseline, 20 patients had no vesicoureteral (VUR) and one had grade II unilateral VUR. Postoperative evaluation revealed no cases of de novo VUR and the patient with preinjection VUR had complete resolution of the reflux. Ultrasound showed 5 (23.8%) patients with hydronephrosis before BTX-A injection and only one (4.8%) at the followup evaluation (p=0.066). After treatment, 9 (42.8%) patients became dry, 11 (52.4%) were improved and one (4.8%) had no improvement. Improved patients received antimuscarinic treatment and 8 (38.1%) became dry, with a final total continence rate of 80.1%. Cystometric capacity increased from 271 +/- 92 to 390 +/- 1189 ml (p = 0.002), reflex volume varied from 241 +/- 96 to 323 +/- 201 ml (p = 0.020) and maximum detrusor pressure reduced from 66 +/- 39 to 38 +/- 37 cm H2O (p < 0.001). Conclusions: Our results confirm the safety of trigone injections of BTX-A in terms of development of VUR and upper urinary tract damage. Whether they are beneficial for patients with NDO or other causes of voiding dysfunction will need further studies.

When Should Renal Replacement Therapy be Initiated for Acute Kidney Injury?

Acute kidney injury (AKI) is now well recognized as an independent risk factor for increased morbidity and mortality particularly when dialysis is needed. Although renal replacement therapy (RRT) has been used in AKI for more than five decades, there is no standard methodology to predict which AKI patients will need dialysis and who will recover renal function without requiring dialysis. The lack of consensus on what parameters should guide the decision to start dialysis has led to a wide variation in dialysis utilization. A contributing factor is the lack of studies in the modern era evaluating the relationship of timing of dialysis initiation and outcomes. Although listed as one of the top priorities in research on AKI, timing of dialysis initiation has not been included as a factor in large, randomized controlled trials in this area. In this review we will discuss the criteria that have been used to define early vs. late initiation in previous studies on dialysis initiation. In addition, we propose a patient-centered approach to define early and late initiation that could serve as framework for managing patients and for future studies in this area.

Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression

Background. Carbamazepine (Carba) is an anticonvulsant and psychotropic drug used widely for the treatment of intellectual disability and severe pains, but the incidence of hyponatremia is a common related occurrence. This hyponatremia is frequently attributed to a SIADH induced by this drug. It is also known that Carba is used to decrease the urinary volume in Diabetes Insipidus (DI) because it has an antidiuretic effect. Lithium (Li) is one of the most important drugs used to treat bipolar mood disorders. However Li has the undesirable capacity to induce DI. Nowadays, the association of these drugs is used in the treatment of patients with psychiatric and neurological problems. Methods. In vivo and in vitro (microperfusion) experiments were developed to investigate the effect of Carba in the rat Inner Medullary Collecting Duct (IMCD). Results. The results revealed that Carba was able to stimulate the V2 vasopressin receptor-Protein G complex increasing the water permeability (Pf) and water absorption. In vivo studies showed that in rats with lithium-induced DI, Carba decreased the urinary volume and increased the urinary osmolality. AQP2 expression was increased both in normal IMCD incubated with Carba and in IMCD from lithium-induced DI after Carba addition to the diet, when compared with the control. Conclusion. These results showed that the hyponatremia observed in patients using this anticonvulsant drug, at least in part, is due to the Carba capacity to increase IMCD`s Pf and that the Lithium-Carbamazepine association is beneficial to the patient.

The role of vaccines in the control of STDs: HPV vaccines

Prophylactic vaccines for genital human papillomavirus (HPV) infection have been shown to be feasible in animal models, and suitable vaccine material based on virus-like particles can be produced in bulk at reasonable cost. Initiation of phase III clinical trials will follow definition of trial outcome measures through further epidemiological studies, and development-of assays of host protective immunity. Vaccines could in principle eliminate HPV-related disease, as the human race is the only natural host for the relevant papillomaviruses (PVs). Therapeutic vaccines for genital HPV infection are also possible, but have not yet been demonstrated as feasible in practice because the choice of vaccine antigens is difficult, the method of their optimal delivery is uncertain, and the nature of the relevant antiviral immunity is unknown. PV species specificity will require trials to be conducted in man, which will slow definition of an ideal vaccine.

cDNA microarray analysis of differentially expressed genes in penile tissue after treatment with tadalafil

To evaluate differential gene expression in penile tissue after treatment with the phosphodiesterase 5 (PDE5) inhibitor tadalafil, as of the three clinically available PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) used for the treatment of erectile dysfunction (ED), tadalafil has a long half-life and low incidence of side-effects. In all, 32 adult rats were divided into two groups. The control group received 0.5 mL of drinking water alone, while the tadalafil group was treated with tadalafil at a dose of 0.27 mg/kg. At 4 h after treatment with water or tadalafil the rats were killed and the penile tissue was removed. The total RNA was isolated from the penile tissue from both groups and differentially expressed genes were identified by cDNA microarray analysis. To validate the expression data from the microarray analysis, quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry were used. In all, 153 genes were differentially expressed between the control group and the tadalafil group. We validated the microarray results by quantitative PCR for the insulin-like growth factor binding protein 6 (IGFBP-6) gene and the neuronal calcium sensor 1 (NCS-1) gene, both of which were up-regulated in the tadalafil group, and for the natriuretic peptide receptor 1 (NPR-1) gene that was down-regulated in this group. Immunohistochemistry showed localization of the NCS-1 protein in sinusoid trabeculae of the corpus cavernosum in control and tadalafil-treated rats. There was differential expression in 153 genes after tadalafil treatment. Some of these genes such as IGFBP-6, NPR-1 and NCS-1, might result in new targets in the treatment of ED.

Use of an Inflatable Silicone Balloon Improves the Success Rate of Bladder Autoaugmentation at Long-Term Followup

Purpose: Most groups have reported disappointing results with autoaugmentation or detrusor myectomy for low capacity/compliance neuropathic bladders. Failure may be due to an ischemic diverticulum or mucosal shrinkage. We investigated whether a Silimed (R) silicone balloon placed in the bladder after autoaugmentation could prevent these problems, improving surgical results. Materials and Methods: We compared the results of standard bladder autoaugmentation in 12 children (group 1) with those in 10 (group 2) who underwent the same surgery using a bladder conformer. The conformer was a silicone balloon filled with saline that remained in the bladder for 2 weeks. All patients had a neuropathic bladder with poor capacity and compliance, resulting in urinary leakage between catheterizations. Preoperative and postoperative evaluation included a voiding diary, ultrasound, voiding cystourethrogram and urodynamics. Results: In group 1 only 1 patient became dry, 4 had little improvement in continence, 4 remained unchanged and 3 became worse. In group 2, 6 patients (60%) become continent without medication, 2 (20%) become continent with oxybutynin and 2 remained unchanged. Bladder capacity and compliance did not change significantly in group 1. However, in group 2 capacity changed from a mean of 140 to 240 ml and mean +/- SD compliance increased from 15.6 +/- 16.8 to 34.3 +/- 22.8 ml/cm H(2)O (p = 0.02). Conclusions: The inflatable balloon improved our long-term results of bladder auto-augmentation. A larger series may be necessary to confirm procedure efficacy and safety.

The therapeutic potential of recombinant BCG expressing the antigen S1PT in the intravesical treatment of bladder cancer

Purpose: Bacillus Calmette-Guerin (BCG) continues to be employed as the most effective immunotherapy against superficial bladder cancer. We have developed an rBCG-S1PT strain that induces a stronger cellular immune response than BCG. This preclinical study was designed to test the potential of rBCG-S1PT as an immunotherapeutic agent for intravesical bladder cancer therapy. Materials and methods: A tumor was induced in C57BL/6 mice after chemical cauterization of the bladder and inoculation of the tumor cell line MB49. Next, mice were treated by intravesical instillation with BCG, rBCG-S1PT, or PBS once a week for 4 weeks. After 35 days, the bladders were removed and weighed, Th1 (IL-2, IL-12, INOS, INF-gamma, TNF-alpha), and Th2 (IL-5, IL-6, IL-10, TGF-beta) cytokine mRNA responses in individual mice bladders were measured by quantitative real time PCR, and the viability of MB49 cells in 18-hour coculture with splenocytes from treated mice was assessed. In an equivalent experiment, animals were observed for 60 days to quantify their survival. Results: Both BCG and rBCG-S1PT immunotherapy resulted in bladder weight reduction, and rBCG-S1PT increased survival time compared with the control group. There were increases in TNF-alpha in the BCG treated group, as well as increases in TNF-alpha and IL-10 mRNA in the rBCG-S1PT group. The viability of MB49 cells cocultured with splenocytes from rBCG-S1PT-treated mice was lower than in both the BCG and control groups. Conclusions: rBCG-S1PT therapy improved outcomes and lengthened survival times. These results indicate that rBCG could serve as a useful substitute for wild-type BCG. (C) 2010 Elsevier Inc. All rights reserved.

Long-Term Effect of Early Postoperative Pelvic Floor Biofeedback on Continence in Men Undergoing Radical Prostatectomy: A Prospective, Randomized, Controlled Trial

Purpose: The impact of pelvic floor muscle training on the recovery of urinary continence after radical prostatectomy is still controversial. We tested the effectiveness of biofeedback-pelvic floor muscle training in improving urinary incontinence in the 12 months following radical prostatectomy. Materials and Methods: A total of 73 patients who underwent radical prostatectomy were randomized to a treatment group (36) receiving biofeedback-pelvic floor muscle training once a week for 3 months as well as home exercises or a control group (37). Patients were evaluated 1, 3, 6 and 12 months postoperatively. Continence was defined as the use of 1 pad or less daily and incontinence severity was measured by the 24-hour pad test. Incontinence symptoms and quality of life were assessed with the International Continence Society male Short Form questionnaire and the Incontinence Impact Questionnaire. Pelvic floor muscle strength was evaluated with the Oxford score. Results: A total of 54 patients (26 pelvic floor muscle training and 28 controls) completed the trial. Duration of incontinence was shorter in the treatment group. At postoperative month 12, 25 (96.15%) patients in the treatment group and 21 (75.0%) in the control group were continent (p = 0.028). The absolute risk reduction was 21.2% (95% CI 3.45-38.81) and the relative risk of recovering continence was 1.28 (95% CI 1.02-1.69). The number needed to treat was 5 (95% CI 2.6-28.6). Overall there were significant changes in both groups in terms of incontinence symptoms, lower urinary tract symptoms, quality of life and pelvic floor muscle strength (p <0.0001). Conclusions: Early biofeedback-pelvic floor muscle training not only hastens the recovery of urinary continence after radical prostatectomy but allows for significant improvements in the severity of incontinence, voiding symptoms and pelvic floor muscle strength 12 months postoperatively.

Autologous transplantation of adult adipose derived stem cells into rabbit urethral wall

A study was carried out to evaluate the feasibility of autologous adipose derived stem cells (ADSC) transplantation into female rabbits` urethra walls as an alternative to intrinsic urethral regeneration. Inguinal fat pad of 12 New Zealand adult female rabbits were harvested and processed to obtain stromal vascular fraction (SVF). The SVF were platted to isolate ADSC. Before urethral injection, cells were labeled with DiI marker. The urethra wall was injected with 1 x 10(7) autologous cells or saline (sham). The urethra was harvested at 2, 4, and 8 weeks to identify DiI-labeled cells. At 2 and 4 weeks, the ADSCs create a nodule localized in the urethral sub-mucosa. At 8 weeks, the ADSCs spread and integrated with the urethra wall from the initial injection site. This is the first study to demonstrate a successful autologous ADSCs transplantation. It confirms that ADSCs can survive and integrate within the urethral wall.

Is the ultrasound-estimated bladder weight a reliable method for evaluating bladder outlet obstruction?

OBJECTIVE To evaluate the correlation between ultrasound-estimated bladder weight (UEBW) in patients with different degrees of bladder outlet obstruction (BOO). METHODS We evaluated 50 consecutive non-neurogenic male patients with lower urinary tract symptoms (LUTS) referred to urodynamic study (UDS). All patients self-answered the International Prostate Score Symptoms (IPSS) questionnaire. After the UDS, the bladder was filled with 150 mL to determine UEBW. Patients with a bladder capacity under 150 mL, a previous history of prostate surgery or pelvic irradiation, an IPSS score <8, a bladder stone or urinary tract infection were excluded. After a pressure-flow study, the Schafer linear passive urethral resistance relation nomogram was plotted to determine the grade of obstruction: Grades I-II/VI were defined as mild obstruction, Grades III-IV/VI as moderate obstruction, and Grades V-VI/VI as severe obstruction. RESULTS The UEBW was 51.7 +/- 26.9, 54.1 +/- 30.0 and 54.8 +/- 28.2 in patients with mild, moderate and severe BOO, respectively (P = 0.130). The UEBW allowed us to define four groups: (i) UEBW < 35 g; (ii) 35 g <= UEBW < 50 g; (iii) 50 g <= UEBW < 70 g; and (4) UEBW >= 70 g. We did not find any differences in age, prostate weight, IPSS, PVR, cystometric bladder capacity, presence of detrusor overactive and degree of obstruction in the aforementioned groups. CONCLUSION Despite the fact that some studies have emphasized the value of UEBW as an efficient non-invasive method for evaluating lower urinary tract obstruction, our study suggests that UEBW does not present any individual correlation with LUTS or objective measurements of BOO.