The Role of a Leaky Epithelium and Potassium in the Generation Of

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2010 THE AUTHOR; BJU INTERNATIONAL 2010 BJU INTERNATIONAL Mini Reviews BLADDER SYMPTOMS CAUSED BY LEAKY EPITHELIUM AND POTASSIUM PARSONS

ET AL.

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 BJUIBJU INTERNATIONAL C. Lowell Parsons UC San Diego Medical Center, Department of Surgery/Urology, La Jolla, CA, USA Accepted for publication 25 May 2010

The traditional diagnosis of interstitial What’s known on the subject? and What does the study add? cystitis (IC) only recognizes the severe form This article reviews entirely new concepts concerning the etiology, presentation and of the disease. The far more common early diagnosis of interstitial cystitis. It pulls the information together in a concise fashion that and intermittent phases of the disease are emphasizes there is a radical change taking place in the concepts of what generates not perceived to be part of IC but rather are bladder symptoms. misdiagnosed as urinary tract infection, urethral syndrome, overactive bladder, Primarily this emphasizes that the paradigm for interstitial cysititis and the generation of chronic prostatitis, urethritis, or a type of bladder symptoms is going to change dramatically. The data reviewed shows that the gynecologic pelvic pain (such as symptoms are caused by a leaky epithelium and subsequent diffusion of potassium into endometriosis, vulvodynia, or some type of the tissues causing frequency, urgency, pain and incontinence. This is totally different vaginitis). All of these patient groups from current concepts. actually suffer from the same bladder disease. This disease results from a leaky bladder epithelium and subsequent conclusions derived from these data and not the 10 plus syndromes traditionally potassium leakage into the bladder substantially alter the paradigms for recognized. interstitium that generates the symptoms urology and gynecology in the generation of frequency, urgency, pain or incontinence of frequency, urgency and pelvic pain. All KEYWORDS in any combination. Robust scientiﬁc data the above-mentioned syndromes unite into now support this important concept. These one primary disease process, lower urinary interstitial cystitis, urinary bladder, data will be reviewed herein. The dysfunction epithelium, or LUDE disease, potassium

INTRODUCTION of ‘early IC’, i.e. disease in younger people with beginnings and instead has been channelled less severe symptoms. This opened up the into focusing on patients with late-phase Little was understood about interstitial possibility of diagnosing the disease in disease and all the secondary effects of the cystitis (IC) in 1980. Only its existence and the patients years before they reached its late and disease process. severity of its symptoms were known. Reports severe phases [2]. on IC were present in the literature 150 years Three decades of clinical, basic and earlier, but nothing was understood This is common sense, since IC has to have a translational research experience on concerning its aetiology and diagnosis was beginning and the initial phases of the disease thousands of IC patients at UC San Diego limited to one of exclusion in patients with would logically be milder and probably cause (UCSD) have resulted in a gradual evolution in severe bladder symptoms. In the 20th century intermittent symptoms; yet the traditional my understanding of the pathophysiology of Hunner’s description of the elusive ulcer, diagnostic paradigm ignores these patients IC, its clinical presentation, diagnosis and Bumpus’s description of petechial with early-phase disease (who represent the therapy. The overall view is that the disease haemorrhages after bladder distension, and substantial majority). However, more modern has an insidious development over many John Hand’s excellent treatise on the clinical approaches are currently being adopted. One years from mild, intermittent symptoms to, in aspects of the disease summarized most of unfortunate consequence of this narrow rare cases, classic severe IC. As the disease the knowledge of IC before 1975 [1]. The ﬁrst perspective of IC is that the clinician/ develops in patients, they are assigned modern development in the understanding of researcher has been limited from developing diagnoses by clinicians based on the IC was when Messing popularized the concept new hypotheses based on the actual disease symptoms they are currently expressing, their

BLADDER SYMPTOMS CAUSED BY LEAKY EPITHELIUM AND POTASSIUM

sex, and the specialist they consult. In this classifying the disease. Patients are likely to be Patients with interstitial cystitis have an early phase, the diagnoses can include misdiagnosed and mistreated for perhaps abnormal, leaky epithelium as measured by recurrent UTIs, overactive bladder (OAB), years, and basic researchers who rely on their urea, potassium, fluorescein and rhamnose urethral syndrome, urethritis, prostatitis (in clinicians for input will be diverted into movement across the transitional cell layer almost all cases in men), endometriosis, yeast pathways that greatly restrict the compared with normal asymptomatic vaginitis, vulvadynia or gynaecological development of new knowledge. A generic controls [13–16]. We believe this ‘leaky’ chronic pelvic pain (CPP). Gynaecologists see and more inclusive name like IC is preferable. epithelial dysfunction is probably the many of the patients since women with IC Only as data emerge will modification of the event that initiates the IC cascade of nerve have sexually associated symptom flares (and name of the disease be justified. It would be up-regulation, muscle reactions and tissue dyspareunia) and their menstrual cycle affects sad to see efforts to rename the disease as injury. their IC symptoms [1,3,4]. As a result, a young part of a political rather than a scientific woman whose urinary frequency is not process. perceived by her to be a problem is likely to THE ROLE OF URINARY POTASSIUM IN THE self-refer to a gynaecologist, who will This review will present evidenced-based GENERATION OF BLADDER SYMPTOMS probably attribute her pelvic symptoms to a information to substantiate the fact that gynaecological source. lower urinary dysfunctional epithelium (LUDE) The bladder epithelium is an important barrier appears to be a principal cause of LUTS in men that protects the underlying nerves and Working in partnership with my patients, my and women <60 years old. muscle from toxic urinary solutes. If the understanding of the disease has evolved and mucus is abnormal and the epithelium new discoveries regarding the aetiology of the THE PROTECTIVE ROLE OF THE MUCOSA becomes permeable then urinary metabolites disease have emerged. I have come to believe AND THE MUCOUS LAYER could diffuse into the muscle layer, provoking that there is probably only one primary disease the symptoms of frequency, urgency, pain, process in the lower urinary tract that results Transitional epithelium is a protective barrier incontinence and tissue injury. in the generation of frequency, urgency pain for the bladder interstitium and functions to and incontinence in patients <60 years old. prevent urinary metabolites from interacting One solute in particular, potassium, has the After the age of 60 years, other factors in both with the muscle layer and/or being potential of causing serious reactions. At men (obstruction) and women (e.g. UTI) are reabsorbed and recycled back into the concentrations >8 mEq/L, potassium will also involved in the generation of symptoms. bloodstream, counteracting the function of depolarize nerves and muscles, and if the While the disease runs its course in any one the kidneys. Cell membranes and tight depolarization is prolonged, the cells will die individual, different diagnoses might be junctions are important components of [17]. Potassium concentrations in urine range ascribed to the cause of the symptoms, such the barrier and so is the surface mucus of from 30 to 120 mEq/L, with a mean as UTI, OAB, prostatitis or gynaecological CPP, the umbrella cells, also known as the concentration of 63 mEq/L [13]. Such high but the generation of symptoms is probably glycosaminoglycan layer [5]. This mucus is concentrations would readily diffuse down originating from one problem in the urinary highly anionic because of the sulphated the gradient into the bladder wall and cause bladder: an epithelial dysfunction of the polysaccharides on the glycosaminoglycan reactions. bladder mucosa that results in a loss of the molecules and the sialic acid present in the normal permeability barrier, resulting in a glycoproteins. As a result, water is bound by To test the hypothesis that potassium was a ‘leaky’ epithelium. Coupled with the normally electrostatic attraction to the mucus [6–9] key factor in generating bladder symptoms in high concentrations of urinary potassium, this and forms an ‘unstirred water layer’ [10,11] IC, the potassium sensitivity test (PST) was causes movement of potassium from urine to that blocks the movement of small developed [18]. The PST briefly exposes the bladder interstitium, which results in a molecules down to the cell surface. Research patients to water and then a potassium cascade of reactions, causing symptoms, studies have confirmed that the epithelial solution, and if they selectively responded to tissue injury and disease progression. mucous layer is critical in regulating the the potassium with a reaction of at least 2 (on permeability of urinary solutes into the a six-point scale) they were called positive. Contrary to historical belief, traditional IC bladder wall [5,12]. Patients with IC were tested and compared actually represents only the severe and with asymptomatic control subjects. To date, relatively rare form of this disease process and In both in vitro and in vivo models, including the international literature contains over 35 not a separate problem from the earlier rodents and humans, when the mucous layer published reports on potassium testing in over phases of the disease. of the bladder is chemically injured, there is a 3000 patients with IC/painful bladder marked increase in solute movement across syndrome (PBS) and the data are very robust, Defining a disease by its symptoms rather the epithelium, including water, urea, calcium with 80% of patients with IC testing positive than by its pathophysiology is often done in and potassium [5,12–14]. In normal human [19–25]. Furthermore, several reports included medicine when there is a lack of scientific subjects, the solutes that were examined were data on about 200 normal subjects and the evidence. The current push to rename IC urea and potassium [5,12–14]. These acute test was negative in 98.3% [14,18,26,27]. ‘painful bladder syndrome’ is an example of injuries were reversed with heparin and this: the first symptom many patients pentosanpolysulphate, raising the possibility Additional support for the hypothesis that experience is chronic frequency. Pain cycles that these compounds could be used for potassium is involved in the generation of develop later or not at all. There are several therapy in people with a defective mucous symptoms comes from experimental data dangers with this arbitrary approach to layer. collected in asymptomatic people. These

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human subjects were catheterized and and the bowel will readily compensate for any TABLE 1 Patients not improved vs those who exposed to both sodium and potassium transient elevations of potassium [28]. This is were improved were compared at entry to the injected directly into their bladders and they the basis for using enemas to quickly reduce study and at exit. Improved patients had a did not react to either cation. These same serum potassium concentrations in renal significant drop in their pain responses to the volunteers had their bladder mucus injured by failure. potassium challenge compared with patients instillation of protamine sulphate, and after whose symptoms did not change this treatment they reacted to potassium with POTASSIUM AND THE URETHRA symptoms, but not to sodium. Heparin placed Entry Exit into the bladder reversed the mucus injury During micturition, the urethra is exposed to Patient group n pain pain P and decreased the symptoms from a third high urinary concentrations of potassium and Not improved 68 3.1 2.7 >0.2 exposure to potassium [14]. When the bladder could potentially suffer the same fate as the Improved 85 3.2 1.3 <0.001 mucus is experimentally injured, the bladder if its protective mucous layer became potassium absorption into the bladder wall dysfunctional. Most patients with IC, both increases at the same time that symptoms are men and women, report dysuria [3], and quite generated, and the absorption also decreases likely that potassium is the cause of this Minaglia et al. [31] performed the PST on over (as do symptoms) after the reversal of the symptom. This could also explain dysuria in 100 patients with OAB and found 71% to be injury with heparin [14]. other diseases, such as bacterial urethritis or positive. A clever modification of testing for non-specific urethritis. potassium sensitivity was reported by Daha What would happen to patients’ potassium et al. that employed a urodynamic model sensitivity if they were successfully treated To determine if potassium could cause [19,32]. In brief, patients first underwent and experienced symptom reduction? urethral discomfort, 22 normal male urodynamic testing with saline and then it Logically, it should improve and, if so, it would volunteers were recruited for a double-blind was repeated with a potassium solution. further corroborate the role of potassium study. One-half of the subjects had their Compared with the saline, potassium caused a in the causation of bladder symptoms. To urethras exposed to a 0.4 M solution of mean reduction in bladder capacity (felt to be help answer this question, the PST was potassium and the other half were exposed to due to potassium causing a spasm of the performed on patients before and after sodium via irrigation with a small catheter; muscle) of 15–23% in all patients with IC/PBS pentosanpolysulphate therapy in a large none experienced discomfort to either cation. tested. multicentre trial in North America that They next had their urethras irrigated with evaluated the effect of different doses of drug protamine sulphate to chemically injure the Subsequently, other investigators reported [27]. Patients who did not improve and who urethral mucus. A subsequent irrigation with the same findings and it did not make any had a follow-up PST had no significant sodium caused no symptoms, but potassium difference if the potassium infusion was given change in the PST results, while patients who resulted in burning discomfort in 90% of the before or after the sodium. The results were did improve on treatment had a significant volunteers [29]. Since most patients with IC the same; all patients with IC had reduced drop in their potassium sensitivity (Table 1). have both bladder and urethral discomfort, it bladder capacities when exposed to appears that epithelial dysfunction occurs in potassium [20]. These same researchers tested There is yet another line of experimental both locations. When the permeability barrier both patients with OAB and those with IC and evidence that supports the potassium is abnormal, potassium effects on the tissues the potassium reactions were all positive in hypothesis. If patients have a ‘leaky’ bladder generate symptoms. both groups [20,23]. In their discussion they epithelium and potassium absorbs into the felt the potassium might be directly affecting bladder wall then the amount of potassium in The potassium hypothesis explains all the the muscle of the bladder, causing the their urine would be expected to be lower in IC symptoms experienced by the IC patients and reduced capacity they observed, and was patients with active symptoms. To test this converts IC from a syndrome into a disease, probably due to an epithelial leak of the concept, concentrations of potassium in LUDE. potassium. In addition, they raised the the urine, normalized to creatinine, were possibility that their results suggested that measured in symptomatic IC patients and OAB and IC might not be separate diseases. compared with normal subjects [13]. There POTASSIUM SENSITIVITY IN These urodynamic data are in agreement was a significantly lower potassium SYMPTOMATIC PATIENT POPULATIONS with Minaglia et al.’s PST findings and the concentration in patients (0.51 mEq/mg combination of both their results suggests it creatinine) than in control subjects (0.88 mEq/ As a scientific tool, the PST has provided a is reasonable to consider that patients with IC mg creatinine; P < 0.001). After treatment means to test other symptomatic populations or OAB have one pathological mechanism – that improved symptoms, the potassium for potassium sensitivity, to determine epithelial dysfunction – and a potassium leak concentrations rose significantly to 0.66 mEq/ whether epithelial dysfunction is causing the that provokes tissue reactions. Furthermore, mg creatinine (P = 0.025). If there is symptoms. Traditionally, many lower urinary the fact that >80% of the patients with IC and substantial reabsorption of potassium back tract conditions have been diagnosed on the OAB are women is certainly compatible with into the bloodstream then the serum basis of patient descriptions of symptoms and these two clinical entities being one disease. concentrations of potassium might be severity rather than objective, scientific expected to rise, but this does not occur. The evidence. Consequently, IC has been arbitrarily Another major source of confusion leading to reason is that the large bowel secretes as distinguished from other disorders, such as misdiagnosis of IC is that pain generated by a much potassium in 24 h as do the kidneys, OAB, only by the presence of pain [30]. visceral organ such as the bladder does not

BLADDER SYMPTOMS CAUSED BY LEAKY EPITHELIUM AND POTASSIUM

to the patient it does appear to be a Other gynaecologists have reported TABLE 2 Potassium sensitivity by clinical gynaecological issue. As a result, she will additional studies with similarly high rates of (gynaecologist) diagnosis self-direct to her gynaecologist for what she positive PST results (≥80%) for patients with believes to be a gynaecological problem. The CPP [34–36]. In a large study of more than Clinical diagnosis n PST-positive, n (%) gynaecologist is unlikely to notice the 100 patients with vulvadynia, >80% had a Pelvic pain 93 71 (76) presence of urological symptoms, primarily positive PST [37], and in another report 83% VV 45 37 (82) frequency of urination, as the patient will not of patients (n = 40) were PST-positive [36]. Dyspareunia 28 25 (89) report it. She may think voiding 12–14 times These two studies highlight the fact that UFS 24 18 (75) a day is normal (it is for her), so when asked bladder pain can refer solely to the labia so Endometriosis 22 19 (86) if she has a problem, she will say no. As a that is not perceived to be from the bladder UTI (recurrent) 15 12 (80) result the women who have pain flares nor is the pain affected by bladder filling and Other 31 11 (85) associated with the menstrual cycle will be emptying. IC 4 4 (100) told they have endometriosis, while if the Total 244 197 (81) pain is in the labia they will be diagnosed The conclusions from these studies are quite with vulvadynia, and if it is vaginal they will dramatic. The data show that epithelial be diagnosed with vaginitis. dysfunction and potassium leak cause most localize well. In my experience with thousands of the pelvic pain in the gynaecological of patients, it can refer to any location, from The confusion continues to build when one population; this is a drastic shift in the the navel to the knees. It can be perceived considers the issue of endometriosis. It is well paradigm. The PST proved to be a valuable solely in the left lower quadrant or as diffuse established in gynaecology that patients scientific tool since it was able to provide lower abdominal pain or in the labia, scrotum, with minimal or no endometriosis can be evidence that the bladder was the principal perineum, vaginally peri-rectal, low back or in associated with severe pelvic pain, while pain generator for gynaecological CPP. These the medial aspect of the thighs [3,26]. Most many with severe endometriosis have no results also underscore the fact that bladder patients I have seen do not fit the classic ‘pain symptoms. I say ‘associated pain’ because it pain refers anywhere in the pelvis, perineum, is worse with filling and relieved by emptying has never been scientifically proven that low back, vagina, scrotum, labia or thighs and the bladder’. Many patients sense more of a endometriosis causes any pelvic pain; it is is usually not perceived to be from the chronic pain, burning, discomfort or pressure more or less a convention to simply ascribe bladder. This is a critical point and is in in the pelvis, lower back or thighs not pain to pelvic findings such as adhesions or contradistinction to what many urologists perceived to be from the bladder. endometriosis without proof. In my practice, I still believe, namely that the only pain seen in have seen many patients who have had IC is obvious bladder pain ‘made worse with Yet others experience the pain only during hysterectomies for pelvic pain but who did bladder filling and relieved by emptying’. It is and/or after the act of voiding and might not experience relief. critical to integrate this new knowledge into delay urinating to prevent it [26]. This voiding our paradigm, if IC is to be diagnosed flare is readily explained by increased Also, many of my patients have had diagnoses properly, and if we are to continue discovering potassium leak due to the combination of of vulvadynia, pelvic adhesions and yeast the causes of this disease. osmotic and increased hydrostatic pressure vaginitis from symptoms that were ultimately associated with micturition. It is this referral shown to be from their bladders. This led me The male patient with IC raises another of bladder pain that is responsible for most of to recruit four gynaecologists to determine interesting issue. Almost all men (<50 years of the confusion and misdiagnoses made by with what frequency (if any) the bladder was age) when initially presenting with symptoms urologists and gynaecologists. The fact is that generating the pain in their pelvic pain of frequency, urgency and/or pelvic pain will urological patients with IC and gynaecological population. The studies included screening be diagnosed by almost every primary care patients with CCP have the same symptoms: the patient for IC symptoms with the Pelvic physician and urologist as having prostatitis frequency, urgency, pelvic pain, menstrually Pain, Urgency, and Frequency Questionnaire or CPP syndrome. But men with IC have associated symptom flares, dyspareunia and (PUF) [26], performing a history and physical similar symptoms to women with IC, sexually associated flares (same for the men). examination, conducting a PST and assigning including voiding symptoms, sexually However, a urologist or gynaecologist will a clinical diagnosis using their traditional associated symptom flares and the presence routinely assign a diagnosis to the same criteria. The results were both surprising and of pain anywhere from the navel area to the patient based solely on their specialities, e.g. very interesting: about 81% of the patients thighs, suggesting that perhaps they are one IC, recurrent urinary infection, endometriosis, had positive PSTs and 85% had urological and the same disease [26,38,39]. vulvadynia or yeast vaginitis. symptoms [17,33]. No matter what clinical diagnosis (Table 2) the patient was given – To test this possibility, men clinically The patient herself is in large part responsible CPP, endometriosis, vulvadynia, yeast vaginitis diagnosed with prostatitis were subjected to for these diagnostic problems. Women being – all had the same percentage (80%) of the PST. In all, 84% were positive for followed by gynaecologists for CPP often do positive PSTs. These data imply that the potassium. In a subsequent study in 50 not perceive their bladders to be the source patients with urological IC and those with patients with prostatitis, 77% were of their difficulties, especially as their pelvic gynaecological pelvic pain have the same potassium-positive compared with 0% in 14 pain is affected by their menstrual cycle and disease. This is a dramatic paradigm shift for asymptomatic controls [29]. An additional will usually have dyspareunia or a flare of gynaecology, where IC goes from a rare study reported 84% positive PSTs in 31 their symptoms after sexual activity. Thus diagnosis to the most common cause of CPP. patients [22]. There was a report that

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mistakenly performed the PST using a 100 mL causes depolarization of sensory nerves and 8 Menter JM, Hurst RE, Nakamura N. volume of fluid instead of 40 mL. The control muscles and injures tissue. Thermodynamics of mucopolysaccharide- subjects had an approximately 38% symptom dye binding. III. Thermodynamic and response to plain water from volume This concept is now supported by very robust cooperativity parameters of acridine sensitivity and so no conclusions can be data that have been widely published in the orange-heparin system. Biopolymers drawn from their findings [40]. The PST international literature. IC/PBS, OAB, 1979; 18: 493–505 provides scientific evidence that prostatitis gynaecological CPP, prostatitis, CPPS and 9 Hurst RE. Thermodynamics of the and IC could be on a continuum of the same urethral syndrome have all been shown to partition of chondroitin sulfate- disease process: epithelial dysfunction and have epithelial leak and potassium sensitivity, hexadecylpyridinium complexes in potassium leak, or LUDE. uniting these syndromes into one disease, butanol/aqueous salt biphasic solutions. LUDE. Biopolymers 1978; 17: 2601–8 Patients with urethral syndrome, who are 10 Dietschy JM, Sallee VL, Wilson FA. primarily women, experience flares of Classic IC is not a different disease; it is just Unstirred water layers and absorption frequency, urgency and/or pelvic pain and the severe and rare form of LUDE. The historic across the intestinal mucosa. dysuria in the absence of a bacterial infection. method of separating these syndromes Gastroenterology 1971; 61: 932–4 My experience with these patients led me to arbitrarily according to the different 11 Wilson FA, Sallee VL, Dietschy JM. consider the fact that they were ‘early IC’ [2], symptoms the patient might express can now Unstirred water layers in intestine: rate when the symptoms are less severe and be replaced by evidence-based medicine that determinant of fatty acid absorption from intermittent. To explore this I selected patients relies on the actual pathophysiology of the micellar solutions. Science 1971; 174: with classic urethral syndrome, defined as problem to define the disease. This represents 1031–3 having acute symptom flares for no more a dramatic change in the traditional paradigm 12 Lilly JD, Parsons CL. Bladder surface than 3 months and negative urine cultures [3]. for the generation of bladder symptoms and glycosaminoglycans is a human epithelial When compared with patients with IC, they opens new vistas for scientific discovery. permeability barrier. Surg Gynecol Obstet were younger and had a lower rate of positive 1990; 171: 493–6 PST (55 vs 78%), but they had the same 13 Parsons CL, Greene RA, Chung M, CONFLICT OF INTEREST symptoms and identical locations of pain Stanford EJ, Singh G. Abnormal urinary throughout the pelvis. The potassium potassium metabolism in patients with None declared. reactions in the patients with urethral interstitial cystitis. J Urol 2005; 173: syndrome were significantly less intense than 1182–5 in patients with IC, as would be expected. The REFERENCES 14 Parsons CL, Greenberger M, Gabal L, PST findings in both IC and urethral syndrome Bidair M, Barme G. The role of urinary confirm that they both have epithelial 1 Hand JR. 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