The method can be used in diagnosing the insufficiency of the inner mucus layer of bladder:
It has been expressed throughout the world that the deficient condition of the protective GAG-layer of the bladder, which prevents the penetration of the urinary constituents into the bladder wall, is observed in several pathologic lower urinary tract conditions, such as interstitial cystitis/bladder pain syndrome (IC/BPS), chemo-cystitis and radiation cystitis (e.g. 1). However, there is no widespread method for estimating the condition of the GAG-layer itself, which significantly hinders the possibility of diagnosing these conditions. Due to this, special issues are raised regarding IC/BPS, whose exact medical definition is still under constant discussion and whose diagnosis still lacks accurate methods.
Attempts For Diagnosing the Status of the GAG-layer
The Potassium Sensitivity Test (a.k.a. Parsons-test) uses intravesical instilled potassium chloride solution of 0.4mol concentration to find out if it irritates the bladder. The procedure could prove if the GAG-layer is damaged (leaky). Still, it was not able to present a quantitative result on the extension of the damage; it was time-consuming, expensive, invasive and painful. Moreover, it turned out later that it was not that reliable as it had been thought. It is not recommended according to most guidelines anymore.
This is why the Modified Potassium Sensitivity Test was developed. Using diluted potassium-chloride (0.2mol) results in a less painful process. Measuring the bladder capacity by filling the organ with potassium-chloride and with physiological sodium-chloride solution enables to get a quantitative result; the difference between the two maximal bladder capacities can be measured. The process, on the other hand, is still invasive and time-consuming.
The Lidocaine Challenge Test works the other way around. In this case, the bladder is being filled with lidocaine, and if the pain lessens or ceases to exist, it becomes revealed that its source is indeed the bladder. The process itself is not painful but provides no quantitative data.
All of these methods did have their advantages, but, unfortunately, were invasive, too, and none of them was quantitative and painless at the same time. To overcome these issues, the GAG-layer Integrity Test has been invented.
Painless
Non-invasive
Quantitative
Potassium Sensitivity Test (Parsons)
❌
❌
❌
Modified PST (Daha, Riedl et al.)
❌
❌
✅
Lidocain anesthetic test (Taneja)
✅
❌
❌
GAG-layer integrity test (Lovasz)
✅
✅
✅
Figure 1. A summary of methods examining the status of the GAG-layer
The Principles Behind
It is known that in the case of GAG-layer insufficiency, the cause of the pain is the irritative effect of certain salts and other aggressive constituents in the urine. (Potassium is not the only irritative substance.) It is also a basic observation that the bigger the concentration of these compounds in the urine is, the bigger the effect is, which results in increased pain and urgency of voiding. However, no external salt solution need be instilled into the bladder to examine the status of the GAG-layer: the urine itself can be used as a physiologic, intrinsic salt solution. By affecting the diuresis arbitrarily, we can learn and quantitatively measure the correlation between the bladder capacity and the urine concentration – thus, define the condition of the GAG-layer.
Voiding diaries have been frequently applied at clinical trials evaluating the IC/BPS patients’ response to specific treatments or for differential diagnostic purposes (e.g. v,vi). However, none of these diaries have seemed to make a connection between the fluid intake (thus, the urine concentration) and the voided volume. GAG-layer integrity test, in contrast, is based on examining this correlation.
Doing so, the patients suspected to have IC/BPS – or a deficient GAG-layer – are to fill in a 2-day voiding diary. On Day 1, they have to minimize the fluid intake so that the urine concentration will be high. On Day 2, they have to maximize the fluid intake to dilute the urine. During these two days, the patients are to hold their urine back as long as they can so that the maximum bladder capacity affected by the urine concentration can be learned given that they are asked to measure the volume (or the weight) of each maximal voided volume (called urine portions) during the daytime. (Night-time voiding has proven to be unreliable for the test.)
The difference between the average of the maximal daytime urine portions on the first and the second day provides quantitative information on the condition of the GAG-layer.
In the case of a healthy bladder, the average volume of the urine portions does not show significant differences (less than 30%). In the case of a mild-to-moderate GAG-layer insufficiency, the difference may rise to 30-100%, whereas a difference of more than 100% (up to 400%) represents a severely damaged GAG-layer integrity.
A small difference between the two days' mean voided volumes and small voided volumes on both days represent an end-stage, maximally shrunk bladder. In this case the GAG-layer integrity test cannot be used reliably.
Figure 2. The correlation between the results of the GAG-layer integrity test and the status of the GAG-layer
Compared to the former similar diagnostic methods, the GAG-Layer Integrity Test has significant advantages as follows:
it is non-invasive, pain-free, and cheap to perform;
no solution need be instilled into the bladder for the test;
it provides quantitative information on the status of the GAG-layer;
the patients can perform the test on their own, merely by following the instructions;
Another advantage of the GAG-Layer Integrity test is, that it can be applied not only for diagnosing IC/BPS but also for follow-up purposes. In this way, should the test be performed regularly, the therapist can learn whether the patient responds to the applied treatment and can use it to optimize the frequency of treatments.
GAG-layer Integrity Test has been successfully used in Rózsakert Medical Center, Hungary, for years.
Currently, we are looking for possible partners who could participate in a multicentral clinical trial so that the efficiency of the test can be examined objectively.
Figure 3. The use of the GAG-layer Integrity Test during the treatment and the patient follow-up. This example shows that the patient responded to the instillation therapy, just as well as the time elapsed until the efficiency of the treatment started to become lower
Further Perspectives
Certain conditions, like a bacterial infection, may lead to GAG-layer insufficiency, too. Under normal circumstances, when the condition responsible for the deficiency has been cured and/or fought off, the recovery of the layer starts instantly, without additional medical help.
Thus, GAG-layer insufficiency does not essentially refer to the condition of IC/BPS. However, if the insufficiency persists, or its cause re-occurs several times (such as, in case of recurring urinary tract infections), there is a chance that the early stage of IC/BPS develops. Therefore, identifying any GAG-layer insufficiency may help prevent the occurrence of IC/BPS; it can have a prophylactic function.
Moreover, once the mild insufficiency has been diagnosed, administering GAG-layer replenishments can speed up the reconstruction of the healthy GAG-layer. The test can be applied for follow-up purposes, as well, so that the therapist can constantly monitor the status of the GAG-layer – and the convalescence of the patient.
Finally, it is possible that the test shows a normal GAG-layer in the case of a patient with severe pelvic pain. This may inform the therapist before applying an expensive and time-consuming treatment that the source of the pain might not be the bladder. Further examinations may confirm or deny the suspicion of IC/BPS, which can be important for categorizing the patients, choosing the assumingly most suitable treatment. This process may help the classification of IC/BPS, too.
Conclusion
For the diagnosis of IC/BPS, the treatment of several different lower urinary tract conditions, and for objectively monitor the efficiency of the applied treatment and for following up the affected patients, it appears to be vital to introduce and define the concept of GAG-layer insufficiency. GAG-layer Integrity Test can be considered an exact diagnostic method for this process.
