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Effect of pentosan polysulfate therapy on intravesical potassium sensitivity
ADULT UROLOGY
EFFECT OF PENTOSAN POLYSULFATE THERAPY ON INTRAVESICAL POTASSIUM SENSITIVITY C. LOWELL PARSONS, JOHN FORREST, J. CURTIS NICKEL, ROBERT EVANS, L. KEITH LLOYD, JACK BARKIN, PHILLIP G. MOSBAUGH, DAVID M. KAUFMAN, JOSE M. HERNANDEZ-GRAULAU, LINDA ATKINSON, AND DETLEF ALBRECHT, ON BEHALF OF THE ELMIRON STUDY GROUP
ABSTRACT Objectives. To evaluate further the intravesical potassium sensitivity test (PST) as an indicator of the epithelial leak of interstitial cystitis (IC) and determine whether successful pentosan polysulfate (PPS; Elmiron) treatment is associated with a change in PST results. Most individuals with IC appear to have an abnormally permeable epithelium that allows urinary solutes such as potassium to penetrate to the bladder interstitium, provoking symptoms. Methods. Data were from an optimal dose trial of PPS in IC. Patients underwent a PST before and after a 32-week trial of 300, 600, or 900 mg PPS/day. The response to PPS treatment was measured using the Patient Overall Rating of Improvement in Symptoms scale. The before and after treatment PSTs and Patient Overall Rating of Improvement of Symptoms scores were compared. Results. Of 377 patients with IC at 28 centers, 302 (80%) had a positive PST at entry. Of the 198 patients who completed the study, 153 were PST positive at entry and 92 (60%) showed clinical improvement at exit. Clinically improved patients had significant improvement on the PST analog pain and urgency scales (3.2 to 1.3 and 3.6 to 1.9, respectively; P ⬍0.0001). In contrast, patients with no clinical improvement had no significant change in pain (3.1 to 2.7) or urgency (3.6 to 3.2). Conclusions. PST shows abnormal epithelial permeability in most patients with IC and a significant reduction in this permeability after successful PPS therapy. PST appears to be a valid indicator of epithelial abnormality and a reliable test in the diagnosis of IC. UROLOGY 59: 329–333, 2002. © 2002, Elsevier Science Inc.
T
he evidence is increasing that the pathogenesis of IC involves abnormal permeability of the transitional epithelium.1–11 We have proposed that an epithelial “leak” of urinary potassium into the bladder interstitium results in neurologic activa-
This study was supported by the Alza Corporation (Protocol No. C-97-032). From the Division of Urology, University of California, San Diego, Medical Center, San Diego, California; Urologic Specialists of Oklahoma, Inc. and St. John’s Medical Center, Tulsa, Oklahoma; Department of Urology, Queen’s University, Kingston, Ontario, Canada; Tannenbaum Urologic Associates, Greensboro, North Carolina; Division of Urology, University of Alabama, Birmingham, Alabama; The Male Health Centres, Toronto, Ontario, Canada; Urology of Indiana, Indianapolis, Indiana; Department of Clinical Urology, Columbia College of Physicians and Surgeons, New York, New York; University of Illinois School of Medicine, Peoria, Illinois; Alza Corporation, Mountain View, California Reprint requests: C. Lowell Parsons, M.D., c/o Janell Poehling, Division of Urology, University of California, San Diego, Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8897 Submitted: August 22, 2001, accepted (with revisions): November 1, 2001 © 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
tion and tissue injury, producing the symptoms and progression of IC.1–3,12,13 This epithelial dysfunction model is the basis of our diagnostic test for IC, the potassium sensitivity test (PST),2,3,12 as well as two modes of therapy for IC, intravesical heparin and oral pentosan polysulfate sodium (PPS; Elmiron). Because IC traditionally has been believed to be extremely difficult to diagnose, the potential importance of the PST is significant. We believe most cases of IC go unrecognized because of the variable nature of the disease presentation. IC can present with urgency, frequency, and/or pain, in any combination, and usually is episodic in its early phases. Its bladder-origin pain can refer to locations anywhere in the pelvis.5 As a result, IC is often mistaken for other urologic and gynecologic disorders. In a recent study of PST results in gynecologic populations, we found more than 80% of patients with pelvic pain may have had bladder-origin pain or IC.1 According to the results of PSTs performed 0090-4295/02/$22.00 PII S0090-4295(01)01586-2 329
and reported in close to 1000 patients with IC to date, approximately 80% of patients with IC had a positive PST1–7; false-positive results were rare (less than 2%).2– 6 The use of oral PPS and intravesical heparin in the treatment of IC is based on the hypothesis that the glycosaminoglycan-rich bladder surface mucus is the primary regulator of epithelial permeability and that a structurally similar exogenous sulfated polysaccharide could effectively treat IC by compensating for the dysfunction of an individual’s natural bladder mucus.14 Both intravesical heparin15 and oral PPS16 –19 have been found effective in treating IC. Heparin and PPS are believed to work by replacing or aiding in the recovery of the individual’s dysfunctional bladder mucus, thereby reducing epithelial permeability.14 The efficacy of PPS has been reported to be 28% to 42% for relatively short-term therapy16 –19; longer term PPS therapy (6 to 12 months) is associated with clinical improvement in 70% to 75% of cases.20 These clinical data provide additional evidence supporting the concept of an epithelial dysfunction in IC. Recently, the Alza Corporation evaluated the efficacy of three doses of PPS in a dose-ranging study enrolling large numbers of patients with IC at 28 different centers. This dosing study, the overall results of which have been reported separately,21 offered the opportunity to administer the PST to a large population of diagnosed patients with IC and thus test the validity of the PST as a diagnostic tool. In addition, by administering a second PST after the 32-week treatment period and an assessment of clinical improvement, we could determine whether successful therapy is associated with an improvement in PST results. Finally, because the PSTs were performed by investigators at 28 different sites, the study enabled us to determine whether PST data are similar in the hands of a variety of clinicians. MATERIAL AND METHODS PATIENTS WITH IC Included in the study were patients with IC enrolled in an Alza Corporation prospective, double-blind, optimal-dose trial of PPS (protocol C-97-032) at 28 medical centers. The diagnosis of IC was established using the National Institutes of Health criteria,22 excepting urodynamic studies. Data were collected at entry and at exit. During the study, the patients received no other mode of treatment for IC.
PPS TREATMENT Patients were treated for 32 weeks with PPS at a dose of 300, 600, or 900 mg/day. Each patient’s dosage of PPS was randomized and blinded at entry.
SYMPTOM ASSESSMENT At exit, the patients completed the Patient Overall Rating of Improvement in Symptoms (PORIS) in which they rated the 330
FIGURE 1. Analog scales and questionnaire used in the PST.
overall change in their IC since the start of the study as 0%, 25%, 50%, 75%, or 100% improvement or as “worse.” The PORIS, which has been validated as a good tool for this purpose,16 was the primary measure of outcome used for this study. A rating of at least 50% improvement was considered a significant clinical response to PPS treatment.
POTASSIUM SENSITIVITY TESTING Before the start of treatment and at exit, each patient underwent a PST,2,3,12 according to the following procedure, with the patient unaware of the identity of the two intravesical solutions. Patients’ responses to the water (solution 1) and potassium (solution 2) instillations were rated using analog pain and urgency scales and a questionnaire (Fig. 1). A small catheter (10F pediatric feeding tube) was placed into the bladder and the bladder contents drained. The first of the two solutions given, solution 1, was 40 mL water, infused slowly for 2 to 3 minutes to minimize volume provocation of symptoms. The solution was left indwelling for 5 minutes. Then, the patient was asked to grade any stimulation or increase in urinary urgency and pain on analog scales (Fig. 1), where 0 represented no change and ⫹1 to ⫹5 represented mild, moderate, or severe provocation, respectively. The bladder was then drained. After the water phase, 40.0 mL of a potassium solution (solution 2) was also instilled slowly for 2 to 3 minutes. The potassium solution is prepared by mixing 20 mmol/L of potassium, obtained from the pharmacy, with sterile water. Enough water was added to bring the volume to 50 mL, and then 40 mL of this mixture was instilled. If the patient reported any significant provocation of pain or urgency during the instillation of potassium or shortly thereafter, the procedure was stopped and the bladder drained. This was considered a positive response and was graded as was done with solution 1. If no immediate reaction to solution 2 occurred, the potassium solution was allowed to dwell in the UROLOGY 59 (3), 2002
bladder for 5 minutes, and then the patient’s symptom reaction was graded (Fig. 1). After the potassium solution was removed, the bladder was washed once with 60 mL water. After both solutions had been instilled and removed, the patient was asked whether one solution caused more urgency or more pain than the other. Any difference between the solutions was then graded as mild, moderate, or severe (Fig. 1). A PST was rated positive if the patient’s urgency or pain grade for the potassium solution was at least 2 points greater than 0 and the patient identified the potassium solution as the solution causing more symptoms. If neither solution was associated with any urgency or pain, the PST was considered negative. A patient may report urgency or pain associated with both solutions. Most patients with IC are both volume sensitive and solute sensitive, and they do have pain of bladder origin when they react to both solutions. Such results were rated as indeterminate, however, unless solution 2 (potassium) was more provocative of symptoms than was solution 1 (water); then, the test was considered positive (Fig. 1). Other mixed or indeterminate reactions may indeed indicate potassium sensitivity, but they were rated as negative for the purposes of this study at patient entry and were so reported. When a patient’s initial PST was compared with the exit PST, the PST results were considered “improved” if the exit PST reverted to normal (negative), showed either pain or urgency scale ratings at least 50% lower than at baseline, or showed a total decrease of at least 3 points on the pain and urgency scales combined. In addition, the average PST patient responses on the analog pain and urgency scales at entry and exit were evaluated.
STATISTICAL ANALYSIS For the comparison of two variables, the Student t test was used. For comparisons of three or more variables, analysis of variance (ANOVA) was used. Chi-square analysis was used in the comparisons of the expected frequency of occurrences.
RESULTS PATIENTS In the 377 patients evaluated at baseline, the PST was positive in 302 (80.1%), negative in 51 (13.5%), and indeterminate in 24 (6.4%). Of 203 patients completing the PPS portion of the trial, 153 were PST positive at entry and completed the study with a PST at exit (not all patients consented to an exit PST). OVERALL RESPONSE TO THERAPY According to the PORIS, significant responses to treatment were seen in 92 (60%) of the 153 PSTpositive patients at entry and in 20 (64%) of the 33 PST-negative patients. No significant differences were found between the two groups (P ⬎0.3). PRETREATMENT AND POST-TREATMENT PST RESULTS Among the 153 patients who were PST positive at entry and who underwent an exit PST, the exit PST showed diminished potassium sensitivity in 63 (74.1%) of those who improved clinically according to the PORIS versus 27 (39.7%) of the patients who did not improve clinically. This difUROLOGY 59 (3), 2002
ference was statistically significant (chi-square analysis, P ⬍0.001). The responses to the water challenge averaged 0.73 (pain) and 1.3 (urgency) at entry and 0.64 (pain) and 1.08 (urgency) at exit. On the exit PST, the response to the potassium challenge in the 85 patients who showed clinical improvement on the PORIS averaged 1.3 for pain and 1.9 for urgency. These values represent significant improvement compared with this group’s baseline average values of 3.2 for pain and 3.6 for urgency (ANOVA, P ⬍0.0001). At exit, the 68 patients without clinical improvement had average scores of 2.7 for pain and 3.2 for urgency. These scores were not significantly different from the group’s baseline averages (pain, 3.1; urgency, 3.6) but were significantly higher than those for the group that showed clinical improvement (P ⬍0.0001). EFFECT OF DIFFERENT PPS DOSES ON THE PST The entry PST pain and urgency score was 3.1 and 3.6 for the 300-mg dose group; 3.2 and 3.6 for the 600-mg group; and 3.3 and 3.5 for the 900-mg group, respectively. The exit PST pain and urgency score was 1.7 and 2.3 for the 300-mg group; 1.9 and 2.5 for the 600-mg group; and 2.3 and 2.7 for the 900-mg group, respectively. Within each PPS dose group, the exit PST pain and urgency scores were significantly lower than the entry PST scores (ANOVA, P ⬍0.005). The exit scores were not significantly different among the three dose groups (P ⬎0.3). The overall clinical results of PPS therapy and IC have been reported elsewhere.21 COMMENT In this study, our primary purpose was to seek additional evidence of the role of potassium in IC by testing the hypotheses that most patients with IC have abnormal epithelial permeability, as would be reflected in a positive potassium sensitivity on the PST and that successful treatment would be associated with a reduction of this potassium sensitivity. We also wished to determine whether the PST, if administered by clinicians to patients with IC at a large number of sites, would yield results similar to those already reported. The data provide definitive support for these hypotheses. At the 28 participating sites, 80% of the diagnosed patients with IC were potassium sensitive at study entry. This percentage is identical to previously published reports of potassium sensitivity rates in patients with IC.3–5,12 Furthermore, the potassiumsensitive patients’ PST results improved substantially as their symptoms resolved. Of the patients who responded to PPS therapy, 74.1% showed sig331
nificant improvement in PST results. Only 39.7% of nonresponders showed improved PST results at exit. The data on the average PST analog pain and urgency scores before and after treatment provide additional evidence for the presence of an epithelial dysfunction in most cases of IC. Patients who improved clinically showed significant decreases in their PST pain and urgency scores, and patients who did not respond to therapy showed essentially no change in either pain or urgency. An improvement in PST results appears to correlate with improvement in the symptoms of IC. This result provides significant validation of the PST as a tool for the diagnosis of the epithelial abnormality present in most cases of IC. As we have stated, a PST was considered negative if neither the water solution nor the potassium solution was associated with any urgency or pain. A positive PST was one in which both the analog scales (a 2-point increase for pain or urgency) and the questionnaire indicated that the potassium solution was more provocative of symptoms than the water solution. The more strongly positive the PST, the greater the potassium sensitivity and, likely, the greater the degree of epithelial permeability. As we demonstrated in earlier studies, neither water nor sodium chloride provokes symptoms of pain or urgency in patients with IC or in control subjects whose urothelia have undergone experimental damage; only potassium does so.3,12 The disagreement is considerable concerning the hypothesis of epithelial dysfunction in IC. The principal studies reported to date, however, all demonstrate that a significant permeability alteration is present in patients with IC versus controls.7,8,12,23 We believe that urinary potassium is a major factor in disease initiation and progression in most (80% to 90%) patients with IC. Urinary potassium achieves levels of 40 to 140 mEq/L (mean 70 to 90). At this concentration, potassium will injure most living tissue; except, significantly, transitional cells. Potassium levels of only 12 to 15 mEq/L will depolarize sensory nerves and muscles. The urinary bladder normally protects itself from the potentially toxic levels of potassium during the storage phase of urine; the healthy transitional epithelium is relatively impermeable. The key component in epithelial impermeability seems to be the surface mucus, whose removal or injury results in substantially increased permeability. The results of the current study provide further support for the hypothesis that individuals with IC have a urothelial dysfunction. It is not known whether an epithelial dysfunction operates as a pathogenic mechanism in all patients with IC. Perhaps 10% of patients with IC may have only a neurologic activation for reasons 332
that are not understood and that have nothing to do with the epithelium. The PST is gaining increasing importance as a diagnostic tool for clinicians who are unsure of the etiology of an individual patient’s urgency, frequency, or pelvic pain. In appropriate clinical situations, a significant response to an intravesical potassium challenge, versus a water challenge, is a valid indicator of the presence of IC. The incidence of false-positive results is less than 2%.2– 6 As we would expect, the overall average response of patients with IC to the water challenge was low at both entry (pain, 0.73; urgency 1.3) and exit (pain, 0.64; urgency 1.08). Overall, we consider this a negative response relative to the responses to the potassium challenge as defined in the Material and Methods section. A negative PST does not preclude the diagnosis of IC, however, as false-negative results are always possible. Patients with severe IC may be unable to identify the potassium solution as more provocative of symptoms because they are already maximally stimulated and cannot respond with a perceptible increase in urgency or pain. Another factor that can affect the responses of patients with IC to the potassium test is the presence of substantial volume sensitivity, in addition to solute sensitivity, as a result of neural activation and up regulation in the bladder.24,25 In such a patient undergoing a PST, pain and/or urgency in response to the water solution (solution 1) does not indicate a negative PST, but rather an indeterminate PST (6.4% were indeterminate in this study). To be accurate scientifically, it indicates the presence of volume sensitivity, which probably represents a positive test. Unless the patient is already maximally stimulated, as discussed above, the presence of potassium sensitivity will be revealed when the patient compares the two solutions. The PST should be considered positive if the patient experiences greater symptom provocation by potassium than by water. In such cases, the patient’s pain and/or urgency grades for solution 2 will be at least 2 points greater than 0, and the patient’s responses to the questionnaire will identify solution 2 as the one that provoked more symptoms. Teichman and Neilsen-Omeis,4 in reporting a greater response to PPS in patients who were potassium sensitive than in those who were potassium negative, have suggested that the results of potassium sensitivity testing might predict the therapeutic response of a patient with IC. The results of our study and theirs, however, cannot be directly compared. Their criterion for a response to PPS was at least a 25% improvement on the PORIS; ours was at least a 50% improvement on the PORIS. In this study, we were not able to demonstrate that positive potassium sensitivity testing preUROLOGY 59 (3), 2002
dicted therapy outcome; both potassium-positive and potassium-negative groups did well in therapy. Although we believe that a positive PST indicates the presence of an epithelial abnormality, a negative PST does not preclude it. The rate of falsenegative results for the PST is not known. For this reason, and as the current data illustrate, PPS therapy should never be ruled out on the basis of a negative PST. We strongly recommend proceeding to standard IC therapy if the clinician believes the PST-negative patient has the disease. REFERENCES 1. Parsons CL, Bullen M, Kahn BS, et al: The gynecological presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol 98: 127–132, 2001. 2. Parsons CL: Potassium sensitivity test. Tech Urol 2: 171–173, 1996. 3. Parsons CL, Stein PC, Bidair M, et al: Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. Neurourol Urodyn 13: 515–520, 1994. 4. Teichman JM, and Nielsen-Omeis BJ: Potassium leak test predicts outcome in interstitial cystitis. J Urol 161: 1791– 1796, 1999. 5. Parsons CL, Zupkas P, and Parsons JK: Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 57: 428 – 433, 2001. 6. Chambers GK, Fenster HN, Cripps S, et al: An assessment of the use of intravesical potassium in the diagnosis of interstitial cystitis. J Urol 162(3 Pt 1): 699 –701, 1999. 7. Kuo HC: Urodynamic results of heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc 100: 309 –314, 2001. 8. Parsons CL, Lilly JD, and Stein PC: Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 145: 732–735, 1991. 9. Erickson DR, Herb N, Ordille S, et al: A new direct test of bladder permeability. J Urol 164: 419 – 422, 2000. 10. Chelsky MJ, Rosen SI, Knight LC, et al: Bladder permeability in interstitial cystitis is similar to that of normal volunteers: direct measurement by transvesical absorption of 99m technetium-diethylenetriaminepentaacetic acid. J Urol 151: 346 –349, 1994. 11. Lavelle JP, Meyers SA, Ruiz WG, et al: Urothelial pathophysiological changes in feline interstitial cystitis: a human model. Am J Physiol Renal Physiol 278: F540 –F553, 2000.
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12. Parsons CL, Greenberger M, Gabal L, et al: The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 159: 1862–1867, 1998. 13. Vizzard MA: Up-regulation of pituitary adenylate cyclase-activating polypeptide in urinary bladder pathways after chronic cystitis. J Compar Neurol 420: 335–348, 2000. 14. Parsons CL: Epithelial coating techniques in the treatment of interstitial cystitis. Urology 49(suppl 5A): 100 –104, 1997. 15. Parsons CL, Housley T, Schmidt JD, et al: Treatment of interstitial cystitis with intravesical heparin. Br J Urol 73: 504 –507, 1994. 16. Parsons CL, Benson G, Childs SJ, et al: A quantitatively controlled method to prospectively study interstitial cystitis and which demonstrates the efficacy of pentosanpolysulfate. J Urol 150: 845– 848, 1993. 17. Mulholland SG, Hanno P, Parsons CL, et al: Pentosan polysulfate sodium for therapy of interstitial cystitis: a doubleblind placebo-controlled clinical study. Urology 35: 552–558, 1990. 18. Parsons CL, and Mulholland SG: Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol 138: 513– 516, 1987. 19. Holm-Bentzen M, Jacobsen F, Nerstrom B, et al: A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 138: 503– 507, 1987. 20. Hanno PM: Analysis of long-term Elmiron therapy for interstitial cystitis. Urology 49(suppl 5A): 93–99, 1997. 21. Nickel JC, Barkin J, Forrest J, et al: Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium (PPS) for interstitial cystitis (IC). J Urol 165(5 suppl): 67, 2001. 22. Gillenwater JY, and Wein AJ: Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis. National Institutes of Health, Bethesda, Maryland, August 28 –29, 1987. J Urol 140: 203–206, 1988. 23. Buffington CAT, and Woodworth BE: Excretion of fluorescein in the urine of women with interstitial cystitis. J Urol 158: 786 –789, 1997. 24. Moss NG, Harrington WW, and Tucker MS: Pressure, volume, and chemosensitivity in afferent innervation of urinary bladder in rats. Am J Physiol 272: R695–R703, 1997. 25. Christmas TJ, Rode J, and Chapple CR, et al: Nerve fibre proliferation in interstitial cystitis. Virchows Archiv A Pathol Anat 416: 447– 451, 1990.
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EFFECT OF PENTOSAN POLYSULFATE THERAPY ON INTRAVESICAL POTASSIUM SENSITIVITY C. LOWELL PARSONS, JOHN FORREST, J. CURTIS NICKEL, ROBERT EVANS, L. KEITH LLOYD, JACK BARKIN, PHILLIP G. MOSBAUGH, DAVID M. KAUFMAN, JOSE M. HERNANDEZ-GRAULAU, LINDA ATKINSON, AND DETLEF ALBRECHT, ON BEHALF OF THE ELMIRON STUDY GROUP
ABSTRACT Objectives. To evaluate further the intravesical potassium sensitivity test (PST) as an indicator of the epithelial leak of interstitial cystitis (IC) and determine whether successful pentosan polysulfate (PPS; Elmiron) treatment is associated with a change in PST results. Most individuals with IC appear to have an abnormally permeable epithelium that allows urinary solutes such as potassium to penetrate to the bladder interstitium, provoking symptoms. Methods. Data were from an optimal dose trial of PPS in IC. Patients underwent a PST before and after a 32-week trial of 300, 600, or 900 mg PPS/day. The response to PPS treatment was measured using the Patient Overall Rating of Improvement in Symptoms scale. The before and after treatment PSTs and Patient Overall Rating of Improvement of Symptoms scores were compared. Results. Of 377 patients with IC at 28 centers, 302 (80%) had a positive PST at entry. Of the 198 patients who completed the study, 153 were PST positive at entry and 92 (60%) showed clinical improvement at exit. Clinically improved patients had significant improvement on the PST analog pain and urgency scales (3.2 to 1.3 and 3.6 to 1.9, respectively; P ⬍0.0001). In contrast, patients with no clinical improvement had no significant change in pain (3.1 to 2.7) or urgency (3.6 to 3.2). Conclusions. PST shows abnormal epithelial permeability in most patients with IC and a significant reduction in this permeability after successful PPS therapy. PST appears to be a valid indicator of epithelial abnormality and a reliable test in the diagnosis of IC. UROLOGY 59: 329–333, 2002. © 2002, Elsevier Science Inc.
T
he evidence is increasing that the pathogenesis of IC involves abnormal permeability of the transitional epithelium.1–11 We have proposed that an epithelial “leak” of urinary potassium into the bladder interstitium results in neurologic activa-
This study was supported by the Alza Corporation (Protocol No. C-97-032). From the Division of Urology, University of California, San Diego, Medical Center, San Diego, California; Urologic Specialists of Oklahoma, Inc. and St. John’s Medical Center, Tulsa, Oklahoma; Department of Urology, Queen’s University, Kingston, Ontario, Canada; Tannenbaum Urologic Associates, Greensboro, North Carolina; Division of Urology, University of Alabama, Birmingham, Alabama; The Male Health Centres, Toronto, Ontario, Canada; Urology of Indiana, Indianapolis, Indiana; Department of Clinical Urology, Columbia College of Physicians and Surgeons, New York, New York; University of Illinois School of Medicine, Peoria, Illinois; Alza Corporation, Mountain View, California Reprint requests: C. Lowell Parsons, M.D., c/o Janell Poehling, Division of Urology, University of California, San Diego, Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8897 Submitted: August 22, 2001, accepted (with revisions): November 1, 2001 © 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
tion and tissue injury, producing the symptoms and progression of IC.1–3,12,13 This epithelial dysfunction model is the basis of our diagnostic test for IC, the potassium sensitivity test (PST),2,3,12 as well as two modes of therapy for IC, intravesical heparin and oral pentosan polysulfate sodium (PPS; Elmiron). Because IC traditionally has been believed to be extremely difficult to diagnose, the potential importance of the PST is significant. We believe most cases of IC go unrecognized because of the variable nature of the disease presentation. IC can present with urgency, frequency, and/or pain, in any combination, and usually is episodic in its early phases. Its bladder-origin pain can refer to locations anywhere in the pelvis.5 As a result, IC is often mistaken for other urologic and gynecologic disorders. In a recent study of PST results in gynecologic populations, we found more than 80% of patients with pelvic pain may have had bladder-origin pain or IC.1 According to the results of PSTs performed 0090-4295/02/$22.00 PII S0090-4295(01)01586-2 329
and reported in close to 1000 patients with IC to date, approximately 80% of patients with IC had a positive PST1–7; false-positive results were rare (less than 2%).2– 6 The use of oral PPS and intravesical heparin in the treatment of IC is based on the hypothesis that the glycosaminoglycan-rich bladder surface mucus is the primary regulator of epithelial permeability and that a structurally similar exogenous sulfated polysaccharide could effectively treat IC by compensating for the dysfunction of an individual’s natural bladder mucus.14 Both intravesical heparin15 and oral PPS16 –19 have been found effective in treating IC. Heparin and PPS are believed to work by replacing or aiding in the recovery of the individual’s dysfunctional bladder mucus, thereby reducing epithelial permeability.14 The efficacy of PPS has been reported to be 28% to 42% for relatively short-term therapy16 –19; longer term PPS therapy (6 to 12 months) is associated with clinical improvement in 70% to 75% of cases.20 These clinical data provide additional evidence supporting the concept of an epithelial dysfunction in IC. Recently, the Alza Corporation evaluated the efficacy of three doses of PPS in a dose-ranging study enrolling large numbers of patients with IC at 28 different centers. This dosing study, the overall results of which have been reported separately,21 offered the opportunity to administer the PST to a large population of diagnosed patients with IC and thus test the validity of the PST as a diagnostic tool. In addition, by administering a second PST after the 32-week treatment period and an assessment of clinical improvement, we could determine whether successful therapy is associated with an improvement in PST results. Finally, because the PSTs were performed by investigators at 28 different sites, the study enabled us to determine whether PST data are similar in the hands of a variety of clinicians. MATERIAL AND METHODS PATIENTS WITH IC Included in the study were patients with IC enrolled in an Alza Corporation prospective, double-blind, optimal-dose trial of PPS (protocol C-97-032) at 28 medical centers. The diagnosis of IC was established using the National Institutes of Health criteria,22 excepting urodynamic studies. Data were collected at entry and at exit. During the study, the patients received no other mode of treatment for IC.
PPS TREATMENT Patients were treated for 32 weeks with PPS at a dose of 300, 600, or 900 mg/day. Each patient’s dosage of PPS was randomized and blinded at entry.
SYMPTOM ASSESSMENT At exit, the patients completed the Patient Overall Rating of Improvement in Symptoms (PORIS) in which they rated the 330
FIGURE 1. Analog scales and questionnaire used in the PST.
overall change in their IC since the start of the study as 0%, 25%, 50%, 75%, or 100% improvement or as “worse.” The PORIS, which has been validated as a good tool for this purpose,16 was the primary measure of outcome used for this study. A rating of at least 50% improvement was considered a significant clinical response to PPS treatment.
POTASSIUM SENSITIVITY TESTING Before the start of treatment and at exit, each patient underwent a PST,2,3,12 according to the following procedure, with the patient unaware of the identity of the two intravesical solutions. Patients’ responses to the water (solution 1) and potassium (solution 2) instillations were rated using analog pain and urgency scales and a questionnaire (Fig. 1). A small catheter (10F pediatric feeding tube) was placed into the bladder and the bladder contents drained. The first of the two solutions given, solution 1, was 40 mL water, infused slowly for 2 to 3 minutes to minimize volume provocation of symptoms. The solution was left indwelling for 5 minutes. Then, the patient was asked to grade any stimulation or increase in urinary urgency and pain on analog scales (Fig. 1), where 0 represented no change and ⫹1 to ⫹5 represented mild, moderate, or severe provocation, respectively. The bladder was then drained. After the water phase, 40.0 mL of a potassium solution (solution 2) was also instilled slowly for 2 to 3 minutes. The potassium solution is prepared by mixing 20 mmol/L of potassium, obtained from the pharmacy, with sterile water. Enough water was added to bring the volume to 50 mL, and then 40 mL of this mixture was instilled. If the patient reported any significant provocation of pain or urgency during the instillation of potassium or shortly thereafter, the procedure was stopped and the bladder drained. This was considered a positive response and was graded as was done with solution 1. If no immediate reaction to solution 2 occurred, the potassium solution was allowed to dwell in the UROLOGY 59 (3), 2002
bladder for 5 minutes, and then the patient’s symptom reaction was graded (Fig. 1). After the potassium solution was removed, the bladder was washed once with 60 mL water. After both solutions had been instilled and removed, the patient was asked whether one solution caused more urgency or more pain than the other. Any difference between the solutions was then graded as mild, moderate, or severe (Fig. 1). A PST was rated positive if the patient’s urgency or pain grade for the potassium solution was at least 2 points greater than 0 and the patient identified the potassium solution as the solution causing more symptoms. If neither solution was associated with any urgency or pain, the PST was considered negative. A patient may report urgency or pain associated with both solutions. Most patients with IC are both volume sensitive and solute sensitive, and they do have pain of bladder origin when they react to both solutions. Such results were rated as indeterminate, however, unless solution 2 (potassium) was more provocative of symptoms than was solution 1 (water); then, the test was considered positive (Fig. 1). Other mixed or indeterminate reactions may indeed indicate potassium sensitivity, but they were rated as negative for the purposes of this study at patient entry and were so reported. When a patient’s initial PST was compared with the exit PST, the PST results were considered “improved” if the exit PST reverted to normal (negative), showed either pain or urgency scale ratings at least 50% lower than at baseline, or showed a total decrease of at least 3 points on the pain and urgency scales combined. In addition, the average PST patient responses on the analog pain and urgency scales at entry and exit were evaluated.
STATISTICAL ANALYSIS For the comparison of two variables, the Student t test was used. For comparisons of three or more variables, analysis of variance (ANOVA) was used. Chi-square analysis was used in the comparisons of the expected frequency of occurrences.
RESULTS PATIENTS In the 377 patients evaluated at baseline, the PST was positive in 302 (80.1%), negative in 51 (13.5%), and indeterminate in 24 (6.4%). Of 203 patients completing the PPS portion of the trial, 153 were PST positive at entry and completed the study with a PST at exit (not all patients consented to an exit PST). OVERALL RESPONSE TO THERAPY According to the PORIS, significant responses to treatment were seen in 92 (60%) of the 153 PSTpositive patients at entry and in 20 (64%) of the 33 PST-negative patients. No significant differences were found between the two groups (P ⬎0.3). PRETREATMENT AND POST-TREATMENT PST RESULTS Among the 153 patients who were PST positive at entry and who underwent an exit PST, the exit PST showed diminished potassium sensitivity in 63 (74.1%) of those who improved clinically according to the PORIS versus 27 (39.7%) of the patients who did not improve clinically. This difUROLOGY 59 (3), 2002
ference was statistically significant (chi-square analysis, P ⬍0.001). The responses to the water challenge averaged 0.73 (pain) and 1.3 (urgency) at entry and 0.64 (pain) and 1.08 (urgency) at exit. On the exit PST, the response to the potassium challenge in the 85 patients who showed clinical improvement on the PORIS averaged 1.3 for pain and 1.9 for urgency. These values represent significant improvement compared with this group’s baseline average values of 3.2 for pain and 3.6 for urgency (ANOVA, P ⬍0.0001). At exit, the 68 patients without clinical improvement had average scores of 2.7 for pain and 3.2 for urgency. These scores were not significantly different from the group’s baseline averages (pain, 3.1; urgency, 3.6) but were significantly higher than those for the group that showed clinical improvement (P ⬍0.0001). EFFECT OF DIFFERENT PPS DOSES ON THE PST The entry PST pain and urgency score was 3.1 and 3.6 for the 300-mg dose group; 3.2 and 3.6 for the 600-mg group; and 3.3 and 3.5 for the 900-mg group, respectively. The exit PST pain and urgency score was 1.7 and 2.3 for the 300-mg group; 1.9 and 2.5 for the 600-mg group; and 2.3 and 2.7 for the 900-mg group, respectively. Within each PPS dose group, the exit PST pain and urgency scores were significantly lower than the entry PST scores (ANOVA, P ⬍0.005). The exit scores were not significantly different among the three dose groups (P ⬎0.3). The overall clinical results of PPS therapy and IC have been reported elsewhere.21 COMMENT In this study, our primary purpose was to seek additional evidence of the role of potassium in IC by testing the hypotheses that most patients with IC have abnormal epithelial permeability, as would be reflected in a positive potassium sensitivity on the PST and that successful treatment would be associated with a reduction of this potassium sensitivity. We also wished to determine whether the PST, if administered by clinicians to patients with IC at a large number of sites, would yield results similar to those already reported. The data provide definitive support for these hypotheses. At the 28 participating sites, 80% of the diagnosed patients with IC were potassium sensitive at study entry. This percentage is identical to previously published reports of potassium sensitivity rates in patients with IC.3–5,12 Furthermore, the potassiumsensitive patients’ PST results improved substantially as their symptoms resolved. Of the patients who responded to PPS therapy, 74.1% showed sig331
nificant improvement in PST results. Only 39.7% of nonresponders showed improved PST results at exit. The data on the average PST analog pain and urgency scores before and after treatment provide additional evidence for the presence of an epithelial dysfunction in most cases of IC. Patients who improved clinically showed significant decreases in their PST pain and urgency scores, and patients who did not respond to therapy showed essentially no change in either pain or urgency. An improvement in PST results appears to correlate with improvement in the symptoms of IC. This result provides significant validation of the PST as a tool for the diagnosis of the epithelial abnormality present in most cases of IC. As we have stated, a PST was considered negative if neither the water solution nor the potassium solution was associated with any urgency or pain. A positive PST was one in which both the analog scales (a 2-point increase for pain or urgency) and the questionnaire indicated that the potassium solution was more provocative of symptoms than the water solution. The more strongly positive the PST, the greater the potassium sensitivity and, likely, the greater the degree of epithelial permeability. As we demonstrated in earlier studies, neither water nor sodium chloride provokes symptoms of pain or urgency in patients with IC or in control subjects whose urothelia have undergone experimental damage; only potassium does so.3,12 The disagreement is considerable concerning the hypothesis of epithelial dysfunction in IC. The principal studies reported to date, however, all demonstrate that a significant permeability alteration is present in patients with IC versus controls.7,8,12,23 We believe that urinary potassium is a major factor in disease initiation and progression in most (80% to 90%) patients with IC. Urinary potassium achieves levels of 40 to 140 mEq/L (mean 70 to 90). At this concentration, potassium will injure most living tissue; except, significantly, transitional cells. Potassium levels of only 12 to 15 mEq/L will depolarize sensory nerves and muscles. The urinary bladder normally protects itself from the potentially toxic levels of potassium during the storage phase of urine; the healthy transitional epithelium is relatively impermeable. The key component in epithelial impermeability seems to be the surface mucus, whose removal or injury results in substantially increased permeability. The results of the current study provide further support for the hypothesis that individuals with IC have a urothelial dysfunction. It is not known whether an epithelial dysfunction operates as a pathogenic mechanism in all patients with IC. Perhaps 10% of patients with IC may have only a neurologic activation for reasons 332
that are not understood and that have nothing to do with the epithelium. The PST is gaining increasing importance as a diagnostic tool for clinicians who are unsure of the etiology of an individual patient’s urgency, frequency, or pelvic pain. In appropriate clinical situations, a significant response to an intravesical potassium challenge, versus a water challenge, is a valid indicator of the presence of IC. The incidence of false-positive results is less than 2%.2– 6 As we would expect, the overall average response of patients with IC to the water challenge was low at both entry (pain, 0.73; urgency 1.3) and exit (pain, 0.64; urgency 1.08). Overall, we consider this a negative response relative to the responses to the potassium challenge as defined in the Material and Methods section. A negative PST does not preclude the diagnosis of IC, however, as false-negative results are always possible. Patients with severe IC may be unable to identify the potassium solution as more provocative of symptoms because they are already maximally stimulated and cannot respond with a perceptible increase in urgency or pain. Another factor that can affect the responses of patients with IC to the potassium test is the presence of substantial volume sensitivity, in addition to solute sensitivity, as a result of neural activation and up regulation in the bladder.24,25 In such a patient undergoing a PST, pain and/or urgency in response to the water solution (solution 1) does not indicate a negative PST, but rather an indeterminate PST (6.4% were indeterminate in this study). To be accurate scientifically, it indicates the presence of volume sensitivity, which probably represents a positive test. Unless the patient is already maximally stimulated, as discussed above, the presence of potassium sensitivity will be revealed when the patient compares the two solutions. The PST should be considered positive if the patient experiences greater symptom provocation by potassium than by water. In such cases, the patient’s pain and/or urgency grades for solution 2 will be at least 2 points greater than 0, and the patient’s responses to the questionnaire will identify solution 2 as the one that provoked more symptoms. Teichman and Neilsen-Omeis,4 in reporting a greater response to PPS in patients who were potassium sensitive than in those who were potassium negative, have suggested that the results of potassium sensitivity testing might predict the therapeutic response of a patient with IC. The results of our study and theirs, however, cannot be directly compared. Their criterion for a response to PPS was at least a 25% improvement on the PORIS; ours was at least a 50% improvement on the PORIS. In this study, we were not able to demonstrate that positive potassium sensitivity testing preUROLOGY 59 (3), 2002
dicted therapy outcome; both potassium-positive and potassium-negative groups did well in therapy. Although we believe that a positive PST indicates the presence of an epithelial abnormality, a negative PST does not preclude it. The rate of falsenegative results for the PST is not known. For this reason, and as the current data illustrate, PPS therapy should never be ruled out on the basis of a negative PST. We strongly recommend proceeding to standard IC therapy if the clinician believes the PST-negative patient has the disease. REFERENCES 1. Parsons CL, Bullen M, Kahn BS, et al: The gynecological presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol 98: 127–132, 2001. 2. Parsons CL: Potassium sensitivity test. Tech Urol 2: 171–173, 1996. 3. Parsons CL, Stein PC, Bidair M, et al: Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. Neurourol Urodyn 13: 515–520, 1994. 4. Teichman JM, and Nielsen-Omeis BJ: Potassium leak test predicts outcome in interstitial cystitis. J Urol 161: 1791– 1796, 1999. 5. Parsons CL, Zupkas P, and Parsons JK: Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 57: 428 – 433, 2001. 6. Chambers GK, Fenster HN, Cripps S, et al: An assessment of the use of intravesical potassium in the diagnosis of interstitial cystitis. J Urol 162(3 Pt 1): 699 –701, 1999. 7. Kuo HC: Urodynamic results of heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc 100: 309 –314, 2001. 8. Parsons CL, Lilly JD, and Stein PC: Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 145: 732–735, 1991. 9. Erickson DR, Herb N, Ordille S, et al: A new direct test of bladder permeability. J Urol 164: 419 – 422, 2000. 10. Chelsky MJ, Rosen SI, Knight LC, et al: Bladder permeability in interstitial cystitis is similar to that of normal volunteers: direct measurement by transvesical absorption of 99m technetium-diethylenetriaminepentaacetic acid. J Urol 151: 346 –349, 1994. 11. Lavelle JP, Meyers SA, Ruiz WG, et al: Urothelial pathophysiological changes in feline interstitial cystitis: a human model. Am J Physiol Renal Physiol 278: F540 –F553, 2000.
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12. Parsons CL, Greenberger M, Gabal L, et al: The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 159: 1862–1867, 1998. 13. Vizzard MA: Up-regulation of pituitary adenylate cyclase-activating polypeptide in urinary bladder pathways after chronic cystitis. J Compar Neurol 420: 335–348, 2000. 14. Parsons CL: Epithelial coating techniques in the treatment of interstitial cystitis. Urology 49(suppl 5A): 100 –104, 1997. 15. Parsons CL, Housley T, Schmidt JD, et al: Treatment of interstitial cystitis with intravesical heparin. Br J Urol 73: 504 –507, 1994. 16. Parsons CL, Benson G, Childs SJ, et al: A quantitatively controlled method to prospectively study interstitial cystitis and which demonstrates the efficacy of pentosanpolysulfate. J Urol 150: 845– 848, 1993. 17. Mulholland SG, Hanno P, Parsons CL, et al: Pentosan polysulfate sodium for therapy of interstitial cystitis: a doubleblind placebo-controlled clinical study. Urology 35: 552–558, 1990. 18. Parsons CL, and Mulholland SG: Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol 138: 513– 516, 1987. 19. Holm-Bentzen M, Jacobsen F, Nerstrom B, et al: A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 138: 503– 507, 1987. 20. Hanno PM: Analysis of long-term Elmiron therapy for interstitial cystitis. Urology 49(suppl 5A): 93–99, 1997. 21. Nickel JC, Barkin J, Forrest J, et al: Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium (PPS) for interstitial cystitis (IC). J Urol 165(5 suppl): 67, 2001. 22. Gillenwater JY, and Wein AJ: Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis. National Institutes of Health, Bethesda, Maryland, August 28 –29, 1987. J Urol 140: 203–206, 1988. 23. Buffington CAT, and Woodworth BE: Excretion of fluorescein in the urine of women with interstitial cystitis. J Urol 158: 786 –789, 1997. 24. Moss NG, Harrington WW, and Tucker MS: Pressure, volume, and chemosensitivity in afferent innervation of urinary bladder in rats. Am J Physiol 272: R695–R703, 1997. 25. Christmas TJ, Rode J, and Chapple CR, et al: Nerve fibre proliferation in interstitial cystitis. Virchows Archiv A Pathol Anat 416: 447– 451, 1990.
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