The potassium sensitivity test: a predictor of treatment response in interstitial cystitis

OBJECTIVE: To determine whether the potassium sensitivity test (PST) can be used to predict the response to treatment with intravesical sodium hyaluronate in patients with interstitial cystitis. PATIENTS AND METHODS: Thirty-eight patients diagnosed with interstitial cystitis were recruited; each had a PST, carried out in a double-blind fashion, followed by six weekly doses of intravesical sodium hyaluronate. The patients were assessed before and after treatment using a self-administered interstitial cystitis symptom index (CSI) and problem index (PI). The clinical response was defined as none (<25% improvement in clinical symptoms), mild (>25%), moderate (50-75%) and excellent (>75%). RESULTS: The PST was positive in 23 and negative or indeterminate in 13 patients; two patients withdrew from the study. Overall 20 of 36 (55%) patients reported an improvement after six doses of intravesical sodium hyaluronate, but 17 (74%) with a positive PST improved, compared to only five (22%) with a negative test (P = 0.03). There was an improvement in the CSI after treatment in both groups, but a significant improvement in the PI only in patients with a positive PST (P = 0.01). The magnitude of change for the CSI and PI was significantly greater in the positive than in the negative group (CSI, P = 0.043; PI, P < 0.001). There were no major complications. Three patients complained of pain after the test, and two with a positive and one with a negative PST developed a urinary tract infection. CONCLUSIONS: Although the role of the PST in the diagnosis of interstitial cystitis requires further clarification, the test helps to predict the response to treatment with glycosaminoglycan-substitution therapy.     

Abnormal urinary potassium metabolism in patients with interstitial cystitis

PURPOSE: If most patients with interstitial cystitis (IC) have epithelial leakage allowing urinary K to penetrate the interstitium and provoke symptoms, urinary K should be lower in untreated patients than in healthy subjects and it should increase with successful heparinoid treatment. This study tested these hypotheses. MATERIALS AND METHODS: Na, K and creatinine (Cr) were determined in spot urine samples from new, symptomatic, untreated patients with IC meeting all National Institute of Diabetes and Digestive and Kidney Diseases clinical diagnostic criteria, returning patients with IC reporting 50% or greater symptom improvement after 4 or greater months of oral heparinoid therapy and control subjects, and in 24-hour urine samples from new untreated patients and controls. RESULTS: In spot urine specimens of 37 new patients with IC K-to-Cr ratios were significantly lower than in 18 controls (0.51 vs 0.88 mg/mg Cr, p = 0.001). A total of 50 successfully treated patients with IC had significantly higher K-to-Cr ratios than those in 37 new patients (0.66 vs 0.51 mg/mg Cr, p = 0.025). Na-to-Cr ratios in the 3 groups were not significantly different. In 24-hour urine specimens 30 new patients had lower average K (31.0 vs 46.2 mEq/l, p = 0.01) and lower K-to-Cr ratios (0.43 vs 0.52 mg K/mg Cr, p = 0.01) than in 47 controls, while Na was not significantly different. CONCLUSIONS: Our finding of lower urinary K in new, untreated patients supports the concept of abnormal epithelial permeability and K absorption in IC. Higher urinary K in successfully treated vs untreated patients may reflect decreasing urinary K absorption due to mucosal repair and a resulting decrease in epithelial permeability. K/mg Cr appears accurate for normalizing urinary K.     

Abnormal pedal thermoregulation in interstitial cystitis

Isolated cold stress tests were used to evaluate the thermoregulatory capacity in the feet of 19 patients with interstitial cystitis (IC) and of 11 healthy volunteer control subjects. Mean pedal skin temperature fell more rapidly in the IC group as compared with controls; significant differences were found at 10-min (P = 0.002) and 20-min (P = 0.0008) cooling. Mean skin temperature remained lower in the IC group throughout the study. Sixteen feet (42%) in the IC group and five (22%) of the control feet failed to return to within 2°C of baseline temperature during the 20-min recovery period. These findings may reflect abnormal vasomotor control in the IC group and, if so, may be indicative of increased spinal sympathetic activity in interstitial cystitis.     

The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain

The traditional diagnosis of interstitial cystitis (IC) only recognizes the severe form of the disease. The far more common early and intermittent phases of the disease are not perceived to be part of IC but rather are misdiagnosed as urinary tract infection, urethral syndrome, overactive bladder, chronic prostatitis, urethritis, or a type of gynecologic pelvic pain (such as endometriosis, vulvodynia, or some type of vaginitis). All of these patient groups actually suffer from the same bladder disease. This disease results from a leaky bladder epithelium and subsequent potassium leakage into the bladder interstitium that generates the symptoms of frequency, urgency, pain or incontinence in any combination. Robust scientific data now support this important concept. These data will be reviewed herein. The conclusions derived from these data substantially alter the paradigms for urology and gynecology in the generation of frequency, urgency and pelvic pain. All the above-mentioned syndromes unite into one primary disease process, lower urinary dysfunction epithelium, or LUDE disease, and not the 10 plus syndromes traditionally recognized.     

Abnormal glycosylation of Tamm‐Horsfall protein in patients with interstitial cystitis

OBJECTIVE

To confirm abnormal glycosylation of Tamm‐Horsfall protein (THP) in patients with interstitial cystitis (IC).

PATIENTS, SUBJECTS AND METHODS

The sialic acid content of THP, a critical component of its biological activity, is reduced in patients with IC. N‐glycan shows reduced levels of high molecular weight tri‐ and tetra‐antennary sialylated oligosaccharides. These results are supported by quantitative monosaccharide analysis of neutral and amino sugars in patients vs control subjects. THP was isolated from urine samples of 23 patients with IC and 24 control subjects by salt precipitation. The sialic acid contents were measured using 1,2‐diamino‐4,5‐methylene dioxybenzene‐high performance liquid chromatography analysis. For N‐glycan profiling, purified THP was treated with peptide:N‐glycosidase F to release N‐glycans. The purified N‐glycans were labelled with 2‐aminobenzamide and were profiled by high‐pH anion exchange chromatography (HPAEC) with fluorescence detection. The neutral and amino sugars were determined by HPAEC with pulsed amperometric detection.

RESULTS

The total sialic acid in patients was half of that in controls. There was a pattern of reduced level of high molecular weight sialylated oligosaccharide in 17 of 23 patients vs four of 24 controls. The total neutral and amino sugars showed a ≈30% reduction in patients. The mean (sem ) for the controls was 133.79 (6.51) vs 94.76 (6.67) nmol/200 µg of THP for patients (P < 0.001).

CONCLUSIONS

THP in patients with IC has reduced sialylation and overall glycosylation, and by inference, THP has a role in the pathophysiology of IC.     

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.     

Review of intravesical therapies for bladder pain syndrome/interstitial cystitis

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic pain condition characterised by urinary frequency, urgency and pain or discomfort which the patient attributes to the bladder. It is a complex condition to manage and treat and requires a multi-disciplinary and multi-modal approach. As well as lifestyle and behavioural modifications, physical therapy and oral medications, intravesical treatments can be used in the treatment algorithm for BPS/IC. A number of intravesical agents are reviewed in this paper along with the available evidence for their use.     

Surgical management of intractable interstitial cystitis

Interstitial cystitis represents a diagnostic and therapeutic challenge. Most patients can be managed conservatively, but a small number of patients do not respond to conservative therapy and for them surgical treatment is indicated. This article reviews the historical and currently used surgical modalities. Enterocystoplasty is the surgical treatment of choice for intractable interstitial cystitis. The results of enterocystoplasty are satisfactory in approximately 80% of patients. However, no histological findings, such as mast cell density or degree of inflammation, can be used as a preoperative predictor of treatment results. The best results of cystoplasty seem to be achieved in patients who have a small bladder capacity, determined preoperatively under anesthesia. Approximately 10%–20% of patients may not be able to void spontaneously after surgery and require self-catheterization. Because of the unpredictable results, cystoplasty must be recommended with caution for certain patients. There is no evidence to indicate that a supratrigonal cystectomy and substitution cystoplasty offer a therapeutic advantage over augmentation cystoplasty alone. The choice of bowel segment does not affect the final outcome provided that it is tubularized and made spherical in configuration.     

Intravesical potassium sensitivity in patients with prostatitis

PURPOSE: Prostatitis and interstitial cystitis encompass similar symptoms and may be manifestations of a single pathophysiological process in the lower urinary tract. Most patients with interstitial cystitis have urinary epithelial dysfunction, as indicated by a positive intravesical potassium sensitivity test. We used the potassium sensitivity test for the presence of epithelial dysfunction in men with diagnosed prostatitis. MATERIALS AND METHODS: We administered the potassium sensitivity test in men who presented with the signs and symptoms of prostatitis (urgency/frequency and/or pelvic pain) after being diagnosed with prostatitis and receiving at least 1 course of antibiotic treatment administered by a urologist other than one of us. We also surveyed the patients for urinary symptoms and pain locations using 2 self-evaluation questionnaires. RESULTS: A total of 44 patients with prostatitis completed the questionnaires and underwent the potassium sensitivity test. Of the 44 men 37 (84%) had positive potassium sensitivity test results, 89% reported urinary urgency/frequency and 82% reported pain. Pain locations included the perineum, lower abdomen, lower back, penis, testes, scrotum and rectum as well as dysuria and post-void pain. Pain with sexual intercourse was reported by 75% of the patients with prostatitis. CONCLUSIONS: The rate of positive potassium sensitivity test results in patients with prostatitis is almost identical to that reported in those with interstitial cystitis (84% and 79%, respectively), suggesting that prostatitis and interstitial cystitis may be a continuum of lower urinary epithelial dysfunction. Similar to patients with interstitial cystitis, most patients with prostatitis experience pain during sexual intercourse and perceive pain at locations throughout the pelvis. We suggest reclassifying the prostatitis-interstitial cystitis disease process as lower urinary dysfunctional epithelium.     

钾离子敏感试验与间质性膀胱炎PUF评分的相关性研究

目的 探讨钾离子敏感试验(PST)与间质性膀胱炎(IC)盆腔疼痛和尿频、尿急症状(PUF)评分的相关性及意义.方法 IC患者14例.女13例,男1例.平均年龄48岁.临床表现主要为尿频、尿急、膀胱克盈后耻骨上及会阴区疼痛.14例均依据美国糖尿病、消化及肾病协会(NIDDK)IC诊断标准确诊.采用膀胱水囊扩张后碳酸氢钠、利多卡因及肝素钠灌注治疗.治疗前后均行PST评分和PUF评分,并分析二者之间的关系.结果 14例患者治疗前后PST评分中位数分别为4.0、1.0,PUF评分中位数分别为27.5、13.5,治疗前后差异均有统计学意义(P<0.01).PST评分与PUF评分呈正相关(治疗前rs=0.868,t=4.418,P=0.001;治疗后rs=0.779,t=4.300,P=0.001).结论 PST和PUF评分在IC中表现出一致性,可单独作为IC诊断、鉴别诊断、病情严重程度及治疗效果判定的重要指标.     

Autonomic response to stress in interstitial cystitis

PURPOSE: Previous studies have documented elevations in indices of sympathetic activity in cats and humans with interstitial cystitis (IC). To examine potential autonomic dysregulation in IC we examined the effects of a laboratory mental stress challenge on blood pressure and heart rate (HR) in patients with IC and healthy controls. MATERIALS AND METHODS: A total of 14 female patients with IC and 14 age matched controls participated in a laboratory session, including a 25-minute mental stress challenge. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR were measured at intervals before, during and following the stressor. The level of chronic stress, symptom severity and pain at voiding were assessed. RESULTS: Mean age was 49 years (range 32 to 66). The resting HR of patients with IC (82.02 bpm) was significantly higher than that of controls (63.31 bpm, p = 0.0001). There was also suggested evidence of elevated resting DBP in patients with IC (p = 0.07) but no significant difference in mean resting SBP. Autonomic arousal elicited by the laboratory stressor did not differ between the groups and subjects in each group perceived the task as equally stressful. Patients with IC had significantly elevated HR at each time point compared with controls (p <0.0001) with an average mean difference +/- SD between the groups of 19.5 +/- 4.0 (main effect for group p <0.0001). Although consistent increases in SBP and DBP were observed in patients after baseline, these differences were not significant. CONCLUSIONS: Patients with IC had an increased HR at baseline and throughout a laboratory mental stress challenge compared to healthy age matched women. No differences in HR or blood pressure reactivity were observed between the 2 groups.     

Psychological profile of Taiwanese interstitial cystitis patients

Objectives:   The correlation between anxiety and interstitial cystitis has, as best we know, not yet been reported on. The present study investigated the psychological profile, including anxiety and depression, of patients suffering from interstitial cystitis (IC).
Methods:   A total of 47 IC patients, all of whom met National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIDDK) criteria, plus a group of 31 age-matched, asymptomatic women received a structured interview on depression (Hamilton Rating Scale for Depression) and also on anxiety symptoms (Hamilton Rating Scale for Anxiety). IC patients also completed questionnaires relating to IC symptom severity, including urgency and frequency (visual analog scale) and O'Leary Sant index.
Results:   A total of 85% of our IC patients featured significant affective symptoms. The average depression scores were 16.6. Fifteen patients (31.9%) featured mild depressive symptoms, five (10.6%) had mild to moderate and 20 (42.6%) had moderate to severe depression symptoms. The mean anxiety score was 21.0, with 21 (44.7%), nine (19.1%) and 17 (36.2%) patients revealing mild, mild to moderate, and moderate to severe anxiety symptoms, respectively. Further, IC patients reported a significantly greater extent of depression and anxiety than was the case for controls. Pain scale and O'Leary Sant index were significantly correlated to anxiety and depression score.
Conclusions:   Most of our IC patients feature significant depression and anxiety. The extent of affective symptoms would appear to correlate well with IC symptom severity.     

A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis

OBJECTIVE

To report a multicentre, community based open‐label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate in the treatment of patients with the clinical diagnosis of interstitial cystitis (IC). Chondroitin sulphate is a naturally occurring glycosaminoglycan (GAG) in the bladder mucus layer and changes in this GAG have been implicated in the pathogenesis of IC, and small single‐centre studies have suggested that intravesical chondroitin sulphate may have efficacy in IC.

PATIENTS AND METHODS

Patients with IC were treated with sodium chondroitin sulphate (Uracyst®, Stellar Pharmaceuticals Inc., London ON, Canada) solution 2.0% via urinary catheter weekly for 6 weeks and then monthly for 16 weeks for a total of 10 treatments. The primary efficacy endpoint was the percentage of responders to treatment as indicated by a marked or moderate improvement on a seven‐point patient Global Response Assessment (GRA) scale at week 10 (4 weeks after the initial six treatments) compared with baseline. A major secondary efficacy endpoint (durability) was the percentage of responders on the GRA scale after 10 treatments. Additional secondary efficacy objectives were differences from baseline in Patient Symptom/Problem Index scores over the course of the treatment compared with baseline.

RESULTS

In all, 47% of the 53 enrolled patients with long standing moderately severe IC (mean [sd , range] diagnosis of IC 3.0 [3.4, 0.1–16] years; duration of symptoms 9.2 [9.2, 1–39] years; baseline symptom score 14.2 [3.2]) were responders at week 10. At 24 weeks, 60% were responders. There was a statistically and clinically significant decrease in the mean (sd ) symptom and bother scores from baseline at 10 weeks and 24 weeks, at 9.0 (4.3) and 8.1 (5.0), respectively (P < 0.001). There were no significant safety issues during the study.

CONCLUSIONS

This multicentre community based real‐life clinical practice study suggests that intravesical chondroitin sulphate may have an important role in the treatment of IC and validates the rationale for a randomized placebo‐controlled trial.     

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.