Uronate peaks and urinary hyaluronic acid levels correlate with interstitial cystitis severity

PURPOSE: Levels of uronate, a basic component of urothelial glycosaminoglycans, are increased in urine specimens of patients with interstitial cystitis with severe symptoms. In this study we examined the urinary glycosaminoglycan profile and correlated the profile and urinary hyaluronic acid (a glycosaminoglycan) levels with symptom severity. MATERIALS AND METHODS: Urine specimens and completed O'Leary-Sant interstitial cystitis symptom and problem indexes questionnaires were obtained from 29 patients with interstitial cystitis, 14 normal individuals, and 14 patients with other benign pelvic and bladder conditions. Patients with interstitial cystitis were divided into group 1-1 or both indexes less than 50% maximum score, and group 2-both indexes 50% of maximum score or greater. All patients met the National Institutes of Diabetes and Digestive and Kidney Diseases criteria except regarding glomerulation. In a followup study 30 urine specimens were collected from 8 patients with interstitial cystitis and from 4 normal individuals during 12 months. The urinary glycosaminoglycan profile was determined by gel filtration chromatography. Glycosaminoglycan peaks were analyzed by polyacrylamide gel electrophoresis. Urinary hyaluronic acid levels were determined by the hyaluronic acid test. RESULTS: Group 2 urine specimens contained 3 uronate peaks, whereas urine specimens from normal individuals and patients in group 1 contained 1 or 2 peaks. Peak 1 consisted of macromolecular glycosaminoglycans whereas peaks 2 and 3 contained oligosaccharides. Urinary hyaluronic acid levels were 3 to 4-fold increased in group 2. Glycosaminoglycan profile and hyaluronic acid levels detected interstitial cystitis severity with 83% sensitivity, and 89.7% and 74.4% specificity, respectively. Interstitial cystitis urothelial cells/tissues also over expressed hyaluronic acid synthase 1 (which synthesizes hyaluronic acid) compared to normal urothelial cells/tissues. In the followup study urinary uronate levels, glycosaminoglycan profile and hyaluronic acid levels detected patients with severe symptoms with 73% sensitivity and 87% to 94% specificity. In both studies uronate, glycosaminoglycan profile and hyaluronic acid levels significantly correlated with interstitial cystitis severity (p <0.001). CONCLUSIONS: Urinary glycosaminoglycan profile, uronate content and hyaluronic acid levels are potentially useful markers for monitoring interstitial cystitis severity, and are likely to be involved in interstitial cystitis pathophysiology.     

Clinical and urodynamic experience with intravesical hyaluronic acid in painful bladder syndrome associated with interstitial cystitis

Introductionfew studies have been carried out on therapeutic options in patients with painful bladder syndrome associated with interstitial cystitis. The aim is to verify the safety and effectiveness of treatment with sodium hyaluronate through intravesical instillation in patients with painful bladder syndrome.Materials and methodsa series of 18 female patients is presented, with a mean age of 51 years and prior diagnosis of painful bladder syndrome, who were treated by means of the weekly infusion of an intravesical solution of 40 mg of sodium hyaluronate in sterile solution, over a period of eight weeks. The patients were examined clinically and urodynamically prior to their inclusion in the study and eight months after the instillations had concluded.Resultsthere was a statistically significant improvement in the urodynamic parameters and in the symptoms measured quantitatively by means of the questionnaire “Pelvic Pain and Urgency/Frequency” between the baseline situation and after the vesical instillation of sodium hyaluronate in patients with painful bladder syndrome. There was no toxicity arising from the treatment, given that no adverse effects were recorded in relation to it.Conclusionthe clinical use of intravesical hyaluronic acid in patients with painful bladder syndrome possibly associated with interstitial cystitis has been demonstrated. The clinical improvement is also associated both with increased bladder capacity and improved bladder sensitivity. Tolerance was excellent. Clinical tests that more profoundly evaluate the therapeutic potential of this drug in this type of patients are required.     

Treatment of refractory interstitial cystitis

Interstitial cystitis is the most therapeutically frustrating condition of the urinary tract. The vast array of treatments available clearly indicates that none is particularly effective. As the majority of patients fail to experience a significant and prolonged response to standard treatments, new options are frequently being developed. These include the oral administration of cimetidine, the intravesical use of hyaluronic acid and BCG, and total cystectomy with the formation of a continent urinary diversion. Unfortunately, the acceptance of many new treatments is based on incomplete evaluation, and this has resulted in a confusing array of disparate alternatives. Effective and durable treatment will not be available until the nature of the disease is better understood and the mechanisms of action of current therapies are elucidated.     

Impact of intravesical hyaluronic acid and chondroitin sulfate on bladder pain syndrome/interstitial cystitis

Introduction and hypothesis

Intravesical instillations of hyaluronic acid (HA) and chondroitin sulfate (CS) may lead to regeneration of the damaged glycosaminoglycan layer in interstitial cystitis/bladder pain syndrome (IC/BPS).

Methods

Twenty-two patients with IC/BPS received intravesical instillations (40?ml) of sodium HA 1.6% and CS 2.0% in 0.9% saline solution (IALURIL?, IBSA) once weekly for 8?weeks, then once every 2?weeks for the next 6?months.

Results

The score for urgency was reduced from 6.5 to 3.6 (p?=?0.0001), with a reduction in pain scores from an average of 5.6 to 3.2 (p?=?0.0001). The average urine volume increased from 129.7 to 162?ml (p?p?p?p?Conclusion The treatment appeared to be effective and well tolerated in IC/BPS in this initial experience.     

A combined intravesical therapy with hyaluronic acid and chondroitin for refractory painful bladder syndrome/interstitial cystitis

The aims of this study were to evaluate the efficacy and tolerability of intravesical instillations of high-molecular-weight hyaluronic acid (HA) 1.6% and chondroitin sulfate (CS) 2.0% in patients with refractory painful bladder syndrome/interstitial cystitis (PBS/IC) and to observe their impact on Quality of Life. Twenty-three women were enrolled. They received bladder instillations with HA and CS weekly for 20 weeks and then monthly for 3 months. Mean follow-up after completion of therapy was 5 months. We observed a significant improvement in urinary symptoms on voiding diaries and Visual Analogue Scale for frequency (p = 0.045), urgency (p = 0.005), and pain (p = 0.001). The O'Leary-Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index resulted in a significant improvement in both scores (p = 0.004 and 0.01, respectively). The Pelvic Pain and Urgency/Frequency Symptom Scale only showed significant improvement in the symptom score (p = 0.001). This promising experience seems to offer an additional therapeutic option in patients with refractory PBS/IC.     

Intravesical hyaluronic acid and chondroitin sulphate for bladder pain syndrome/interstitial cystitis: long-term treatment results

Introduction and hypothesis

Reconstruction of the glycosaminoglycan layer plays a role in the successful treatment of bladder pain syndrome/interstitial cystitis (BPS/IC). Intravesical instillations of hyaluronic acid (HA) and chondroitin sulphate (CS) have given results in the short term. We hypothesise that these benefits continue in the longer term.

Methods

With the aim of evaluating this therapy over a longer period we treated 12 BPS/IC patients refractory to other treatments with a combination of HA 1.6?% and CS 2.0?% over a period of 3?years assessing symptoms and quality of life using a visual analogue scale, 3-day voiding diaries and validated questionnaires.

Results

Improvements in bladder function were sustained for 3?years (mean number of daily voids decreased from 17.8 at baseline to 15.5 at 9?months and 11.9 at 3?years, and mean volume per void from 136.8?ml at baseline to 143.9?ml at 9?months and 180.9?ml at 3?years). Quality of life assessments confirmed these improvements.

Conclusions

Intravesical instillations of HA and CS produced a sustained improvement of the symptomatology, up to 3?years, in patients with BPS/IC refractory to previous treatments. Further confirmation would be expected from larger controlled trials.     

Treatment of interstitial cystitis with the neodymium-YAG laser

Five patients with severe interstitial cystitis that had not responded to conventional means of therapy were treated with the neodymium-YAG laser. Of the 5 patients 4 demonstrated cessation of severe bladder pain and frequency of urination within several days after therapy. These patients also were studied objectively by measuring bladder capacity, which was found to be increased over-all. Complication rates from this modality of therapy were extremely low. The patients have been followed for 3 to 15 months after treatment and to date have had no recurrent symptoms of severe interstitial cystitis, although some have had mild recurrent voiding symptoms.     

Intravesical hyaluronic acid for interstitial cystitis/painful bladder syndrome: A comparative randomized assessment of different regimens

Objectives: To compare the clinical effectiveness of different regimens of intravesical hyaluronic acid instillation for patients with interstitial cystitis/painful bladder syndrome. Methods: A total of 60 patients (age 16–77 years) diagnosed with interstitial cystitis/painful bladder syndrome were enrolled in this prospective, randomized study. A total of 30 patients were assigned to receive four weekly intravesical instillations of 40 mg of hyaluronic acid followed by five monthly instillations (hyaluronic acid‐9 group). Another 30 patients received 12 intravesical instillations of 40 mg hyaluronic acid every 2 weeks (hyaluronic acid‐12 group). Symptomatic changes after hyaluronic acid treatments were assessed using Interstitial Cystitis Symptom and Problem Indexes, pain visual analog scale, functional bladder capacity, frequency and nocturia in voiding diary, maximum flow rate, voided volume, postvoid residual volume, and Quality of Life Index at 1, 3 and 6 months. Results: Of the 60 patients, 59 were evaluable at the end of the study. The Interstitial Cystitis Symptom Index, Interstitial Cystitis Problem Index and total score, pain visual analog scale, functional bladder capacity, maximum flow rate, and Quality of Life Index improved significantly after 6 months in both groups. The frequency and voided volume improved significantly only in the hyaluronic acid‐12 group. However, patients with moderate and marked improvement were clinically similar in both groups. The measured variables did not differ between the two groups over the course of the study. Conclusion: No significant difference was noted in the therapeutic effect between two hyaluronic acid instillation regimens for treatment of interstitial cystitis/painful bladder syndrome patients. Both groups showed significant improvement in symptom scores and Quality of Life Index.     

Sequential hydrodistension and intravesical instillation of hyaluronic acid under general anaesthesia for treatment of refractory interstitial cystitis: a pilot study

Pilot study looking at the combination of general anaesthetic hydrodistension and intravesical hyaluronic acid for treatment of refractory interstitial cystitis. Twenty-three treatment refractory patients were recruited with an average age 53.4 years. All underwent general anaesthetic cystoscopy, hydrodistension and instillation of hyaluronic acid (40 mg/50 ml). The bladder was then subsequently drained with the patient awake. Two initial treatments were carried out a month apart and duration between treatments increased depending upon symptom response. In the responders, the average number of treatments was 6.6 (median 4.5), duration between treatments was 3.1 months (median 2.6) and follow-up 15.8 months (median 16). Seventeen patients (74%) responded with immediate improvement in symptoms. In all responders, healing of ulceration and resolution of inflammation occurred. Average anaesthetic bladder capacity increased in the responder group from an average of 492 ml (median 500 ml) to an average of 776 ml (median 700 ml). Our pilot data suggests sequential hydrodistension and hyaluronic acid treatment under general anaesthesia may be considered for resistant cases of interstitial cystitis, especially those that cannot tolerate the instillation procedure under local anaesthesia. Further prospective trials are required.     

The association of elevated urinary total to sulfated glycosaminoglycan ratio and high molecular mass hyaluronic acid with interstitial cystitis

PURPOSE: A decrease in the glycosaminoglycan (GAG) layer on the urothelium is believed to be one of the possible causes of interstitial cystitis. Consequently, GAG-like substances and hyaluronic acid (HA) have been prescribed for treating this condition. To delineate the possible role of GAG and HA in the interstitial cystitis disease process, we compared the urinary levels of total GAGs (sulfated + non-sulfated), sulfated GAGs and HA in interstitial cystitis patients and normal controls. We also examined different HA species present in the urine of interstitial cystitis patients. MATERIALS AND METHODS: The total GAG and sulfated GAG levels in urine specimens of normal individuals (n = 20) and interstitial cystitis patients (n = 25) were determined by utilizing the carbazole reaction assay and the Farndale method, respectively, and were expressed as microg./mg. creatinine. Urinary HA levels were measured by applying the HA test and were expressed as ng./mg. creatinine. Gel filtration column chromatography was used to examine the profile of urinary GAGs and HA species. RESULTS: Total urinary GAGs were 2.5 to 4-fold elevated in interstitial cystitis patients with moderate to severe symptoms (Group 2; 76.2 +/- 24.8) when compared with those in normal individuals (19.9 +/- 2.5) and patients with mild symptoms (Group 1; 30.4 +/- 5.1) (p <0.001). Three urinary GAG peaks were detected in both normal and interstitial patients. However, each GAG peak from interstitial cystitis patient urine was 3 to 5-fold higher than that from normal patient urine. The sulfated GAG levels, however, remained unchanged among normal individuals (1.4 +/- 0.22), Group 1 (2.2 +/- 0.96) and Group 2 (1.6 +/- 0.38) patients (p >0.05). Consequently, the ratio of total GAGs to sulfated GAGs was elevated 3 to 3.5-fold in Group 2 patients (49.9 +/- 13.9) in comparison to that in normal individuals (16.7 +/- 2.5) and group 1 patients (14.4 +/- 4.6) (p <0.001). Urinary HA levels were marginally elevated in Group 2 patients (821. 4 +/- 247.9) when compared with those in the normal group (337.3 +/- 106.1) and Group 1 patients (540.9 +/- 166.5). In addition, a distinct high molecular mass HA species was present only in Group 2 patients. CONCLUSIONS: The increased ratio of total GAGs to sulfated GAGs and marginally elevated HA levels in urine indicate that the GAG layer is altered in interstitial cystitis patients. However, these results are in contrast to the accepted concept that a reduction in urothelial GAGs causes interstitial cystitis. The high molecular mass HA species detected in patients with severe symptoms may play a role in the pathophysiology of this disease.     

Treatment of interstitial cystitis with hydrodistention and bladder training

This study aimed to evaluate the efficacy of hydrodistention (HD) and bladder training for interstitial cystitis (IC). From 1997 to 2006, 361 consecutive IC patients were treated by HD, followed by bladder training. Each patient was followed up using a diary for 8 weeks after HD weekly and monthly thereafter. The efficacy of the treatment was evaluated using the average of the voided volumes and the voiding frequency. The mean +/- standard deviation of the pre-HD daytime voided volumes and voiding frequency were 110.0 +/- 47.0 ml and 14.7 +/- 11.0, respectively. Furthermore, the nocturnal values were 173.1 +/- 91.8 ml and 2.8 +/- 1.7, respectively. After 72 weeks post-HD, the 185 patients who completed the follow-up had volumes/frequency of daytime, 306.5 +/- 80 ml and 6.9 +/- 2.1, respectively, and nocturnal, 325.8 +/- 122.4 ml and 1.3 +/- 0.6, respectively. The implementation of HD and bladder training is crucially important for long-term remission among IC patients.     

Intravesical hyaluronic acid treatment for ketamine-associated cystitis: Preliminary results

IntroductionLong-term ketamine abuse may cause variable lower urinary tract symptoms (LUTS) and severe cystitis. The clinical features of ketamine-associated cystitis (KC) are very similar to bladder pain syndrome/interstitial cystitis (BPS/IC). Intravesical administration of hyaluronic acid (HA) is one of the regimens for treating BPS/IC. In this study, we aim to investigate whether intravesical HA therapy may improve the LUTS of patients with KC.Materials and methodsFour female patients and one male patient with KC who failed oral medications were enrolled in this study. HA (Cystistat) at a dose of 40 mg in a volume of 50 mL of phosphate-buffered saline was injected into the bladder on a weekly basis for 6 weeks and then monthly for a further 3 months. Response to therapy was evaluated by the visual analog scale (VAS) for pain, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Treatment efficacy was assessed by comparing the pretreatment and posttreatment mean scores of the five questionnaires using the paired t test.ResultsThe mean age of the patients was 22 ± 1.5 years. The mean duration of ketamine abuse was 68 ± 16.7 months. After intravesical HA therapy for 4 weeks, statistically significant mean decreases in VAS (from 7 to 4.4, p = 0.03), IPSS voiding subscore (from 16.2 to 11.6, p = 0.017), and ICSI (from 16.4 to 13.6, p = 0.016) questionnaire scores were seen. However, only ICSI constantly reduced after 4 weeks of treatment.ConclusionIntravesical HA therapy may have short-term benefits for improving bladder pain and voiding symptoms in patients with KC.     

Intravesical hyaluronic acid and alkalinized lidocaine for the treatment of severe painful bladder syndrome/interstitial cystitis

Introduction and hypothesis

Intravesical instillation of hyaluronic acid (HA) may restore the integrity of glycosaminoglycan layer in patients with painful bladder syndrome/interstitial cystitis (PBS/IC), and the benefit may be improved with addition of alkalinized lidocaine (AL).

Methods

48 women with severe PBS/IC who failed oral medications were enrolled and divided into one trial and two control groups. The trial group received intravesical 40?mg HA, 10?ml of 2?% lidocaine and 5?ml of 8.4?% sodium bicarbonate on a weekly basis for 8?weeks and then monthly for 4?months with a subsequent follow-up of 24?weeks, while the two control groups received 40?mg HA and mixture of 10?ml of 2?% lidocaine and 5?ml of 8.4%sodium bicarbonate respectively following the same procedure. Response to therapy was evaluated by Global Response Assessment, voids per day, Visual Analogue Scale for pain, frequency and urgency, O??leary-Sant Interstitial Cystitis Symptom Index and Problem Index, cystoscopy and bladder capacity.

Results

Overall 45 patients finished this study protocol. The HA + AL group and the AL group showed significant improvement at week 2 (P?<?0.01), while the HA group began to show effect at week 4 (P?<?0.01). There was no improvement in the AL group at week 24 and these patients quitted the study without follow up. Contrarily, the HA + AL and HA group kept on improving till the end of the study without significant difference between the two groups.

Conclusions

Intravesical instillation of HA and AL may provide both immediate and sustained relief of symptoms in severe PBS/IC in this preliminary study.     

Treatment of ulcer and nonulcer interstitial cystitis with sodium pentosanpolysulfate: a multicenter trial

The effect of sodium pentosanpolysulfate (Elmiron) in the treatment of interstitial cystitis was observed in an open controlled multicenter trial. We studied 87 patients with symptoms for more than 2 years at 17 centers in Finland and Sweden. Patient selection was based on the typical chronic symptomatology but the material subsequently was stratified according to objective cystoscopic findings. The medication (400 mg. daily in 2 oral doses) was discontinued after 6 months. The response was evaluated every 4 weeks during treatment and every 3 months thereafter. Most patients responded favorably, many with diminution of pain within only 4 weeks from the start of treatment. The frequency of micturition decreased significantly and the mean volume per void per 24 hours increased in the patients without bladder ulceration but such changes were not found in the patients with ulcer. The bladder capacity was smaller in the ulcer group. In these patients the pre-treatment intensity of pain was somewhat greater than in those without bladder ulcer but the pain was alleviated in both groups and this effect was stable at the 3-month followup. The differences in responses in the 2 groups indicate a probable fundamental difference between ulcerative and nonulcerative interstitial cystitis. Side effects of the drug were few, slight and transient. Therefore, the study indicates that a significant number of patients with interstitial cystitis can be expected to benefit from treatment with sodium pentosanpolysulfate.     

Treatment of bladder pain syndrome and interstitial cystitis: a systematic review

Introduction and hypothesis

Bladder pain syndrome/interstitial cystitis (BPS/IC) has various treatments; however, no standardized treatment has been established. The aim was to analyze different types of treatment of BPS/IC and their effectiveness.

Methods

A literature review with a search strategy for articles related to BPS/IC published between 1990 and 2014 was conducted on MEDLINE, PUBMED, and SCOPUS. Only randomized controlled trials in women were included in the meta-analysis, while other experimental studies were used as bases for a systematic review of the topic. Clinical trial quality was defined according to the Jadad scale.

Results

Of 356 articles, 13 were included in the analysis. The intervention methods were as follows: instillation of hyaluronic acid, botulinum toxin A, intravesical lidocaine, hyperbaric chamber, massage, physiotherapy, phosphate-buffered saline, piroxicam in combination with doxepin, and others. We did not find any treatment with at least two randomized controlled trials for meta-analysis. Among the assessment tools for symptoms of BPS/IC, the most frequently used were the visual analogue scale, voiding record, and the O’Leary–Sant questionnaire.

Conclusion

Existing studies were not able to define the best approach for the treatment of BPS/IC. The lack of standardized treatment may be related to the diversity of interventions used; therefore, further studies with better methodological quality are needed.

     

Therapeutic effects and predictive factors for successful intravesical hyaluronic acid instillation in patients with interstitial cystitis/bladder pain syndrome

ObjectiveHyaluronic acid (HA) is currently used in Taiwan as intravesical instillation for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). This study investigated the therapeutic effects of HA on IC/BPS in the Taiwanese population.Materials and methodsMen and women aged ≥18 years with documented IC/BPS were initially treated with four weekly intravesical HA instillations (treatment time, 1 month) and then with five monthly instillations (total treatment time, 6 months). Clinical assessments included the evaluation of the Visual Analog Scale (VAS) score of bladder pain, O'Leary–Sant Symptom (OSS) score, IC Symptom Index (ICSI), IC Problem Index (ICPI), functional bladder capacity (FBC), uroflowmetry parameters, and global response assessment (GRA). Therapeutic effects were compared between responders (GRA increased ≥ 2 scales) and nonresponders (GRA increased < 2). Multivariate linear analysis was used to determine predictive factor for successful treatment.ResultsA total of 64 patients (3 men and 61 women) with mean age of 49.4 years (range, 20–79) completed the study. Compared with the baseline data, VAS, ICSI, ICPI, OSS score, daytime frequency, nocturia, and FBC all improved at 1 month or 6 months after starting HA treatment. Significantly more improvements in ICSI, ICPI, OSS score, VAS, and FBC were noted in the responders than in the nonresponders at 6 months of treatment. A low-grade glomerulation was the only predictor for successful treatment response to intravesical HA treatment.ConclusionIntravesical HA administrations improved IC symptoms, decreased bladder pain, and decreased frequency after four instillations, and decreased nocturia and increased bladder capacity after completion of all nine instillations. Low-grade glomerulation predicts successful outcome.     

Decreased urinary uronic acid levels in individuals with interstitial cystitis

The pathogenesis of interstitial cystitis currently is unknown. A possible etiology is that the transitional epithelium is defective, leading to molecular leaks that initiate the disease complex. An important surface defense mechanism is the glycosaminoglycans or polysaccharides that line the bladder epithelium and act as a nonspecific antiadherence factor blocking access of bacteria, microcrystals, proteins and ions to the underlying transitional cells. We examined the excretion of urinary macromolecular uronic acid and glycosaminoglycans in normal individuals and those with interstitial cystitis. A total of 37 controls had a mean macromolecular uronic acid level of 56 nmol. per mg. creatinine, compared to 40.2 nmol. per mg. creatinine in 43 patients with active disease (differences were significant, p equals 0.03). The median excretions of glycosaminoglycan uronate for controls and patients were 15.1 and 11.1 nmol. per mg. creatinine, respectively. (There was an over-all tendency to decrease excretion in patients with a p value of 0.06.) Specimens obtained at cystoscopy from patients with active interstitial cystitis had ureteral macromolecular uronic acid levels of 40.5 nmol. uronate per mg. creatinine compared to 43.6 nmol. uronate per mg. creatinine from the bladder. Interstitial cystitis patients had 16.0 nmol. glycosaminoglycan uronate per mg. creatinine compared to 14.6 nmol. per mg. creatinine in normal controls. Neither of these differences was statistically significant. It would appear that there is a tendency to lower macromolecular uronic acid and polysaccharide excretion in individuals afflicted with this syndrome.