The calcification phenomenon has relevant clinical consequences that may compromise stent removal. When indwelling time increases, encrustation prevalence increases proportionally(7,26,29,30) and global encrustation can occur, leading to the use of endourological techniques, extracorporeal lithotripsy or open surgery to resolve these conditions(8,31). Although heavily encrusted stents clearly do pose significant problems, minor encrustations can also challenge the endourologist, particularly if occurring frequently and repetitively(27). Some publications indicate that the mere presence of a biofilm in the stent increase patient’s discomfort and lower urinary tract symptoms (LUTS)(11,32), which may increase inflammation, tissue damage and eventually affect stent removal. To this date, no oral treatment to prevent or decrease stent encrustation have been proposed.
The degree of stent encrustation was strikingly reduced in the experimental group treated with the oral composition, when considering each stent end separated or their sum, as well when adjusting the data for baseline urine pH, age, sex, previous implantation and indwelling duration. Particularly for those stents with a global encrustation value, the difference between the intervention group and placebo yielded a relative risk of 8.2 and this effect was enhanced by baseline pH level.
The microscopic study of the stents indicated that organic matter in the urine (macromolecules or cellular debris) is first deposited on the stent forming a layer (conditioning film) that is several micrometers thick (figure 2, encrustation definition 0(f)). The thickness and composition of the conditioning film depend on the urine composition of the patient.
For patients with non-lithogenic urine (no hypercalciuria, no hyperoxaluria, no hypocitraturia, and a urinary pH between 5.5 and 6.2) and no bacterial colonization of the urine, organic matter deposits can occur, and act as heterogeneous nucleants that support the growth of COM crystals over 2 to 3 months (33,34). This growth is very slow, forming only a thin layer (thickness of several micrometers) (Figure 2). The underlying mechanism may be analogous to the formation of COM stones in renal cavities (33). If a patient has a high level of urinary calcium, then COD crystals may develop.
If bacteria are present, they can colonize the stent surface and grow while embedded in the initially deposited organic matrix (figure 4). The biofilm resulting from infection by urease-producing bacteria increases the urinary pH and leads to the formation of carboxyapatite and magnesium ammonium phosphate crystals (figure 6). Depending on bacterial activity, these crystals can range from small deposits to large concretions, and, in many cases, they obstruct the inflow and outflow through the stent, and make the stent extraction much more difficult for the urologist. The most common bacteria in these deposits is P. mirabilis (35,36). It is interesting to observe how the presence of bacteria on the organic matter layer has been detected, forming the biofilm, but they have not been identified on the magnesium ammonium phosphate crystals, which are clearly infectious. This can be explained considering that the bacteria are installed in the areas between the organic matter and the surface of the crystalline deposit, thus being also protected from the action of antibiotics.
For urine with a pH higher than 6.2 and no bacterial colonization, significant deposits of calcium phosphate can develop depending on the specific conditions. In particular, when the urine has a high calcium concentration, a citrate deficit, and a pH greater than 6.2, large deposits of brushite can build (figure 6) (33,34). Under these conditions, large COD crystals can also occur. When the calcium and magnesium concentrations are low, large hydroxyapatite deposits can develop. For urine with a pH less than 5.5, major deposits of uric acid can develop (figure 5). It is important to point out that, in urinary pH values between 5.5 and 6.2, the crystalline development occurs at such a rate that does not allow the development of large deposits and consequent obstructions.
The multivariate models showed that the formation of deposits in the double J stent ends is a multifactorial process dependent on patient’s previous implantation, duration of the implantation period, baseline pH level, and the use of an oral composition (figure 3). Both oral composition and baseline pH are independent factors that prevent stent encrustation. A mean pH greater than 6.2 during indwelling time increased 12.9 times the risk of global encrustation of a stent end. In addition, the experimental group has a higher urinary pH decrease from baseline to the end of the indwelling period. The fact that the oral composition studied consists in an acidifier (L-methionine) plus an inhibitor (phytin) may account for it, since both components have a synergic effect on reducing urine pH and inhibiting urine crystallization, respectively, which may prevent encrustation (12,18,19).
A better adherence to treatment could add more value to the final data; 37.5% of patients in the placebo group and 30% in the experimental took less than 80% of prescribed doses. Additionally, both intervention and placebo groups lowered their urine pH levels; this may be since hygienic-dietary indications for stent care were given to all participants and to the daily urine pH self-monitoring carried out by both groups. Patients scored their satisfaction with the pH meter with an average of 8 over a 0 to 10 scale.
This study has some limitations. It would be useful if metabolic urine studies were performed prior and after the administration of the oral composition and/or the placebo. However, most of the cases included in our trial came from the emergency room (ER) or from peri-surgical situations, making difficult to collect urine samples for metabolic analysis. In addition, it was considered a possibility of bias in the urinary metabolic parameters due to such hospitalization and surgical interventions. It is a pioneer study, consisting in the first controlled, prospective, randomized and multicenter trial collecting and analyzing 198 stent ends, and for this first assumption of the potential benefits of the proposed therapy, one could consider up to 56 days a short indwelling time. It asks for next steps, which will be a study comprising longer periods to validate the treatment.
Overall, the results observed reveal a significant decrease in global encrustation in the intervention group even in the short period of time applied in this study. We also observe a higher urinary pH decrease in the experimental group, being lower urinary pH a protective factor against encrustation. To our knowledge this is the first report of a potential oral treatment to prevent double J ureteral stent encrustation by changing the urine composition of the patients.