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.     

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.     

Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis

The urgency-frequency syndrome (UFS) (non-bacterial cystitis, interstitial cystitis) may well represent a heterogenous group with several etiologies. This study was based on the hypothesis that one subset of UFS patients has a leaky (to solutes) epithelium and cations such as potassium could thereby diffuse subepithelially and provoke symptoms. It was also hypothesized that normal impermeable transitional epithelium would not allow cations to diffuse across the cells during the K + provocation test and no symptoms would be experienced. If the epithelium was permeable (“leaky”), diffusion would occur and provoke symptoms. Water or 0.4 M KCl was placed intravesically into normal volunteers and interstitial cystitis (IC) patients. Water did not provoke symptoms in either group but KCl provoked 45% of normals and 70% of IC patients. Differences were significant (P < 0.0001). This test provides a valuable diagnostic tool for UFS and a valuable research tool to separate epithelial permeability problems from other subsets of patients. A third group, consisting of 11 IC patients in remission on heparinoid therapy, was also tested and only 18% were provoked by KCl. Four patients with radiation cystitis were also examined and all four (100%) were provoked by the potassium. © 1994 Wiley-Liss, Inc.     

A comparison of multiple urine markers for interstitial cystitis

PURPOSE: We measured several urine markers in 24-hour specimens from patients with interstitial cystitis and healthy controls. For each marker we determined whether the urine level was significantly different in interstitial cystitis and control cases, and whether the marker level correlated with the symptom score. MATERIALS AND METHODS: Study participants included 36 female patients with interstitial cystitis and 36 age matched female volunteers. Multiple urine aliquots were obtained to measure the various markers. RESULTS: Certain markers were significantly increased in interstitial cystitis, including anti-proliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3 and interleukin (IL)-6. Markers significantly decreased in interstitial cystitis were heparin-binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate and methylhistamine. Other markers were not significantly different in the interstitial cystitis and control groups, including total glycosaminoglycans, epitectin, hyaluronic acid, IL-8, IL-1 and nitrates plus nitrites. IGF-1 was undetectable in 24-hour urine samples but spot voided samples from the same interstitial cystitis population had IGF-1 levels similar to previously reported levels. The only significant association of marker with symptom score was a positive correlation of IL-6 with nocturia. For all markers the conclusions were the same whether the marker was normalized to creatinine or to 24 hours. CONCLUSIONS: This study confirmed several previously reported urine alterations in interstitial cystitis, including increased anti-proliferative factor, epidermal growth factor, IGF binding protein-3 and IL-6, and decreased heparin-binding epidermal growth factor-like growth factor and cyclic guanosine monophosphate. Of all markers studied anti-proliferative factor had the least overlap in the interstitial cystitis and control groups, and so it is the most likely candidate to become a diagnostic test.     

Restoring the glycosaminoglycans layer in recurrent cystitis: Experimental and clinical foundations

Restoring the bladder glycosaminoglycans layer has recently been introduced as prophylactic treatment for recurrent urinary tract infections. Herein, we analyze the latest main clinical and experimental studies to support this therapeutic option. An electronic research was carried out in the most common databases in order to identify any published studies. Retrieved studies were categorized as experimental or clinical according to their setting. For the clinical studies, the evidence level was assigned. A total of 13 laboratory studies showed how bladder glycosaminoglycans instillations act: attenuation of the inflammation process, reduction of bladder contraction amplitude and frequency, reduction of epithelium damage, and lower bacterial growth in urine and tissue samples. Likewise, two randomized clinical trials with grade 2 evidence level and two case series with grade 4 evidence level reported glycosaminoglycans as an alternative to reduce episodes and to prolong recurrence time in patients with recurrent urinary tract infections. At least 12 months of follow up was completed. No serious adverse events were reported. Compared with a placebo, in one randomized study a significantly higher maximum cystometric capacity was obtained, whereas in the other study a significant increase in quality of life scores was reported too. An improvement in the urinary symptoms score was reported by the two randomized trials. Although the clinical use of glycosaminoglycans replacement therapy for recurrent urinary tract infections is supported by a small number of clinical studies with different evidence levels, the laboratory studies show that glycosaminoglycans could have a protective role against inflammatory factors, supporting the idea “to restore the glycosaminoglycans bladder layer to prevent chronic disease course”.     

Discovery of morphological subgroups that correlate with severity of symptoms in interstitial cystitis: a proposed biopsy classification system

PURPOSE: We identified morphologically distinct subgroups in interstitial cystitis using cluster analysis and investigated the associations between cluster membership and urinary symptoms. MATERIALS AND METHODS: Of 637 patients enrolled in the Interstitial Cystitis Data Base Study 203 (32%) provided bladder biopsies at baseline screening, representing the focus of this analysis. A cluster analysis algorithm implemented in SAS PROC CLUSTER using standardized distances to measure the dissimilarity of each pair of patients with respect to select histopathological features was used to construct subgroups of these patients. Multivariate regression models for baseline nighttime and 24-hour voiding frequency, urinary urgency and pain were developed, incorporating indicator variables for cluster membership as predictors. Longitudinal urinary symptom profiles during 3 years of followup were also compared among the morphology clusters. RESULTS: Three morphology clusters were identified, corresponding to unique pathological groupings. In cluster C2 7 patients showed multiple pathological features of parenchymal damage, including several inflammatory features. In cluster C1 17 patients was characterized by complete denudation of the urothelium and variable edema. In cluster C0 in 179 patients none of the pathological features were present above the specified thresholds for C2. Cluster membership was significantly associated with baseline nighttime and 24-hour frequency (p <0.001, and with urinary urgency (p = 0.03). These significant increases in baseline symptom severity among clusters from C0 to C1 to C2 persisted throughout the 3 years of followup. CONCLUSIONS: These results suggest an important role for histopathological features in the predictive modeling of interstitial cystitis symptoms.     

Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Hemorrhagic cystitis (HC) is a relatively rare bladder disease with a complex etiology. With the growing number of patients with pelvic radiation therapy, incidence of this disease has risen considerably. Although treatments like hyperbaric oxygen (HBO) had some benefit to improve the symptoms, the optimal treatment of this disease still remains a tough problem. We reported our experience of intravesical hyaluronic acid (HA) and HBO in treating HC and the results seemed interesting. Intravesical HA is easier to do and well tolerated, and it showed a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months. We suggest it as an alternative and potential way in treating HC.

OBJECTIVE

• ? To compare the efficacy of intravesical hyaluronic acid (HA) instillation and hyperbaric oxygen (HBO) in the treatment of radiation‐induced haemorrhagic cystitis (HC).

PATIENTS AND METHODS

• ? In total 36 patients who underwent radiotherapy for their pelvic malignancies and subsequently suffered from HC were randomly divided into an HA group and an HBO group.
• ? Symptoms of haematuria, frequency of voiding and the visual analogue scale of pelvic pain (range 0–10) were evaluated before and after the treatment with follow‐up of 18 months.

RESULTS

• ? All patients completed this study and no obvious side effects of intravesical HA were recorded.
• ? The improvement rate showed no statistical difference between the two groups at 6, 12 and 18 months after treatment.
• ? Decrease of frequency was significant in both groups 6 months after treatment, but was only significant in the HA group 12 months after therapy.
• ? The improvement in the visual analogue scale remained significant in both groups for 18 months.

CONCLUSIONS

• ? Intravesical instillation of HA was as effective in treating radiation‐induced HC as HBO.
• ? It is well tolerated and resulted in a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months.

     

Effect of hyaluronic acid on urine nerve growth factor in cyclophosphamide‐induced cystitis

Objectives: To investigate how hyaluronic acid (HA) affects nerve growth factor (NGF) production and bladder overactivity in a cyclophosphamide (CYP)‐induced cystitis rat model. Methods: Female Sprague–Dawley rats received three intermittent intraperitoneal injections of CYP (75 mg/kg) or saline. Before or after CYP injection, HA was given intravesically and urine NGF was checked with creatinine correction. Bladder function was evaluated by cystometrograms under Zoletil anesthesia. Furthermore, the effect of HA was counteracted with hyaluronidase (HYAL). Bladder structural change was compared among groups with trichrome stain. Results: The intercontraction interval (ICI) significantly decreased in CYP‐injected rats in comparison to the saline‐injected controls. In the CYP‐injected groups, bladder HA instillation significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the saline instillation. NGF production significantly increased in CYP‐injected rats, but decreased significantly with HA treatment. Treatment with HA had a more significant effect on urine NGF and the use of HYAL would eliminate this effect. Specific staining showed mucosa swelling after CYP treatment. Little HA coating on bladder mucosa could be found in HA‐treated rats. Conclusions: Present findings raise the possibility that HA could be an effective treatment for CYP‐related bladder overactivity through the involvement of NGF signaling.     

Prevention of recurrent bacterial cystitis by intravesical administration of hyaluronic acid: a pilot study

OBJECTIVES: To assess the effect of bladder instillations of hyaluronic acid (HA) on the rate of recurrence of urinary tract infection (UTI). PATIENTS AND METHODS: Forty women (mean age 35 years) with a history of recurrent UTI received intravesical instillations of HA (40 mg in 50 mL phosphate-buffered saline) once weekly for 4 weeks then once monthly for 4 months. The UTI status was assessed over a prospective follow-up of 12.4 months and compared with the rates of UTI before instillation, determined by a retrospective review of patient charts covering 15.8 months. RESULTS: After HA treatment no patients had a UTI during the 5-month treatment phase and 28 (70%) were recurrence-free at the end of the follow-up. The mean (sd) rate of UTI per patient-year was 4.3 (1.55) before treatment and 0.3 (0.55) afterward (P < 0.001). The median time to recurrence after HA treatment was 498 days, compared with 96 days beforehand (P < 0.001). The tolerability was excellent, as side-effects were limited to nine patients who reported mild bladder irritation; no patient interrupted the treatment. CONCLUSIONS: In this preliminary study, bladder instillations of HA had a significant effect on the rate of UTI in women with a history of recurrent UTIs. The bladder instillation of HA is an acceptable and promising therapeutic alternative in patients with recurrent UTI. Expanded placebo controlled clinical trials examining this application of HA are currently underway.     

Effect of comestibles on symptoms of interstitial cystitis

PURPOSE: Anecdotal evidence suggests that patients with painful bladder syndrome/interstitial cystitis report symptom exacerbation after consuming particular foods, beverages and/or supplements. We determined the prevalence of the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms and identified particular comestible items more likely to affect such symptoms. MATERIALS AND METHODS: A validated questionnaire designed to detect whether food, beverages and/or supplements have an effect on bladder symptoms was administered to 104 patients meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria for interstitial cystitis. In addition to answering general questions about the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms, subjects were asked to indicate whether each of 175 individual items worsened, improved or had no effect on symptoms. Each response was numerically scored on a scale of -2 to 2 and mean values were generated for each comestible item. RESULTS: Of the surveyed patients with painful bladder syndrome/interstitial cystitis 90.2% indicated that the consumption of certain foods or beverages caused symptom exacerbation. There was no correlation between allergies and the effect of comestibles on symptoms. Patients who reported that specific foods worsened symptoms tended to have higher O'Leary-Sant interstitial cystitis symptom index and problem index, and/or pelvic pain and urgency/frequency patient symptom scale scores. A total of 35 comestible items had a mean score of lower than -1.0, including caffeinated, carbonated and alcoholic beverages, certain fruits and juices, artificial sweeteners and spicy foods. CONCLUSIONS: There is a large cohort of patients with painful bladder syndrome/interstitial cystitis in whom symptoms are exacerbated by the ingestion of specific comestibles. The most frequently reported and most bothersome comestibles were coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners and hot pepper.     

Evaluation of urinary and general symptoms and correlation with other clinical parameters in interstitial cystitis patients

AIMS: Interstitial cystitis (IC) has been deemed by some authors as a local manifestation of a systemic disease, particularly one of the autoimmune disorders. In order to provide an answer to the question whether IC patients do or do not indiscriminately report high scores for various somatic symptoms, we compared University of Wisconsin scores (U-W scores), including both urinary and non-urinary symptoms, for 30 IC female patients and 30 female controls. MATERIALS AND METHODS: A total of 30 female patients with IC and 30 healthy female controls were recruited for the study. All patients had to meet the symptom criteria established by the National Institute for Diabetes and Digestive and Kidney Diseases. Each patient completed a University of Wisconsin symptom scale, after translation (WICS). RESULTS: In the IC group median score was zero for all, but two of the reference symptoms: abdominal cramps and dizziness. All urinary symptoms were significantly increased in IC patients compared to controls. In the control group, the median value of urinary symptoms was zero. The duration of the disease was then related to IC symptoms in the patient group. Among the bladder-related symptoms, a good correlation was found for several specific symptoms and urinary symptoms as a whole. An association could be found between a positive potassium sensitivity test (PST) and burning bladder sensation, as well as pelvic discomfort. CONCLUSIONS: IC patients had significantly higher scores for the seven urinary symptoms compared to controls. The duration of disease was found to be correlated with the group of seven urinary symptoms.     

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.     

Is interstitial cystitis an allergic disorder?: A case of interstitial cystitis treated successfully with anti-IgE

Interstitial cystitis (IC) is a chronic disorder diagnosed by symptomatology of pelvic pain and urinary frequency, which are extremely variable and unpredictable fluctuating among patients. IC has recently been found combined with some allergic disorders and histopathologic abnormalities resembling that of allergic disorders, including mast cell activation, histamine release and eosinophil infiltration. Therefore, it could be cautiously postulated that IC is one of the allergic disorders of the urogenital system. A 28-year-old Caucasian female patient, who was diagnosed with asthma and allergic rhinitis, suffered from bladder symptoms of frequency, urgency and pelvic pain for the past 3 years. The symptoms disturbed her every day and were intractable for treatment. Urologists concluded that she had interstitial cystitis. Specific immunotherapy (SIT) was recommended for her allergic symptoms. While taking specific immunotherapy, she had anaphylaxis. She still had the reaction even with the 1000-fold diluted shot of SIT. Omalizumab was used for her allergic symptoms and possible prevention of anaphylactic reaction to SIT. Interestingly, she reported that her urogenital symptoms had subsided since omalizumab had been started. According to the published literature, we postulate that interstitial cystitis might be one of the IgE mediated, mast cell driven allergic disorders of the urogenital system. Therefore, in this case, the patient's bladder symptoms are successfully controlled primarily by anti-IgE therapy and the improvement could be maintained by SIT. We report, for the first time, a case of interstitial cystitis with allergic rhinitis and asthma, successfully treated by anti-IgE therapy and specific immunotherapy.