Improvement of Urinary Dysfunction After Kidney Transplantation by Administration of the Antimuscarinic Agent—Prospective Randomized Controlled Study

Abstract

Background. 

Bladder dysfunction after kidney transplantation (KTx) impairs the patients' quality of life. We examined the bladder function status perioperatively in patients undergoing KTx and performed a randomized prospective study to determine the efficacy of an antimuscarinic agent, solifenacin, in ameliorating the bladder dysfunction after KTx.

Methods. 

The subjects in this study were 33 patients who underwent KTx at our institution. The patients were divided into two groups: group 1 (n=18), composed of patients who were not treated with any antimuscarinic agent, and group 2 (n=15), composed of patients treated with an antimuscarinic agent. We investigated the actual bladder function status of these patients before and after KTx by the following two methods: (1) video water cystometry and (2) questionnaire study using the Overactive Bladder Symptom Score and King's Health Questionnaire.

Results. 

The cystometry study revealed a significantly greater increase of the maximum cystometric capacity in group 2 than in group 1 (173.0±60.7 mL in group 1 and 260.1±51.0 mL in group 2 [P=0.005]) after KTx. In the questionnaire surveys, the decreases in the scores for all domains were observed 6 weeks after KTx. The scores in group 2 tended to be lower than those in group 1.

Conclusion. 

In all of our patients, the bladder dysfunction status improved dramatically after KTx. In addition, our results suggest that administration of the antimuscarinic agent, solifenacin, may contribute to improvement of the quality of life of patients undergoing KTx.

Kidney transplantation (KTx) has been broadly accepted as the best treatment option for end-stage renal disease (ESRD). However, the mechanism of recovery of the urinary function immediately after KTx is still controversial. In particular, it is still unclear how a dysfunctionalized bladder, not used for long periods of time, begins to function so well immediately after the surgery.

As described by many researchers (^{1, 2}), the longer the duration of renal replacement therapy, such as maintenance hemodialysis, the greater the degree of impairment of the storage function of the urinary bladder. Inoue et al. (¹) emphasized that a small-capacity bladder may increase the likelihood of development of urological problems after KTx, especially, vesicoureteral reflux (VUR). We have also previously reported (²) the results of analysis of bladder function in patients with ESRD; in that study, transplant candidates waiting for KTx frequently showed bladder dysfunction, such as low bladder capacity, low compliance, and also detrusor overactivity (DO). In this study, we examined the status of bladder dysfunction in patients before and after KTx and in addition performed a randomized prospective study to determine the efficacy of an antimuscarinic agent in improving the functions of the dysfunctionalized bladder by the following two methods: (1) video water cystometry (CM) and (2) questionnaire study using King's Health Questionnaire (KHQ) and the Overactive Bladder Symptom Score (OABSS).

RESULTS

Characteristics of Patients

The demographics of the 33 patients are listed in Table 1. There was no significant difference between groups 1 and 2 in any item, such as sex, age, the duration of renal replacement therapy, the type of transplantation, and the blood-type compatibility.

TABLE 1: Patients' background (n=33)

Changes in the Video Water Cystometric Parameters After KTx When Compared With the Values Before KTx

There was no significant difference in the daily urine volume between groups 1 and 2 before and after transplantation (before Tx: group 1, 112.5±164.8 mL/day; group 2, 116.7±180.9 mL/day, P=0.95; after Tx: group 1, 2100±316.2 mL/day; group 2, 2287±419.0 mL/day, P=0.30) during this study period, because all transplantations in this study were performed from living donors (data not shown).

The volume at first sensation (FS; the volume during filling CM at which a patient first becomes aware of the bladder filling) (³) changed from 59.5±38.0 mL before KTx to 118.1±32.1 mL after KTx in group 1 and from 45.6±24.9 mL before the KTx 107.5±49.2 mL after KTx in group 2. There was no significant difference in the FS between groups 1 and 2, either before or after KTx. Moreover, the ΔFS (change in the volume at FS from before to after KTx) also did not differ significantly between the two groups; the ΔFS was 65.2±38.6 mL in group 1 vs. 65.4±53.0 mL in group 2. The maximum cystometric capacity (MC; the volume in patients with normal sensation at which the patient feels he/she can no longer hold back micturition) (³) changed from 118.1±57.0 mL before KTx to 289.6±80.9 mL after KTx in group 1 and from 87.9±30.5 mL before KTx to 335.6±64.9 mL after KTx in group 2. There was no significant difference in the MC between two groups, either before or after the surgery; however, the ΔMC (increase of the MC from before to after KTx) was significantly greater in group 2 when compared with that in group 1; the ΔMC was 173.0±60.7 mL in group 1 vs. 260.1±51.0 mL in group 2 (P=0.005). The bladder compliance increased from 26.4±30.7 mL/cmH₂O before KTx to 46.4±29.5 mL/cmH₂O after KTx in group 1, and 20.6±35.3 mL/cmH₂O before KTx to 66.4±40.9 mL/cmH₂O after KTx in group 2. No significant difference in the bladder compliance before KTx was observed between the two groups (Table 2). Although 78.6% (11/14) of the group 1 patients and 83.3% (10/12) of the group 2 patients showed low bladder compliance (defined as a value of <20 mL/cmH₂O) before KTx, these percentages decreased to 28.3% (2/7) and 0% (0/8) after KTx (data not shown). Table 2 shows abnormal findings of DO and VUR detected by CM. In group 2, the incidence of DO and VUR significantly decreased after KTx (DO before KTx 33.3% vs. after KTx 12.5%; VUR before KTx 26.7% vs. after KTx 12.5%).

TABLE 2: Results of cystometry

Lower Urinary Tract Symptoms After KTx

The prevalence of lower urinary tract symptoms decreased as the postoperative period increased in both groups. After 6 weeks, 81.8% (9/11) of group 1 reported of daytime frequency, 54.5% (6/11) reported of nighttime frequency, and 9.1% (1/11) reported of urgency; on the other hand, in group 2, the corresponding percentages were 85.7% (6/7), 57.1% (4/7), and 0% (0/7; Table 3). Although there were no significant differences in the frequency of any of the lower urinary tract symptoms between two groups, it is noteworthy that “urgency” disappeared in group 2 by 6 weeks after the start of administration of the antimusucarinic agent, despite the high rate of 71.4% before the start of medication.

TABLE 3: Prevalence of lower urinary tract symptoms after kidney transplantation according to the postoperative period

Analysis of the Scores on the KHQ

In the assessment of the patients' quality of life (QOL) using the KHQ, there were obvious improvements in all domains in both groups during the period of our study. Six weeks after the operation, the scores for each domain were as follows: 20.5±24.5 in group 1 vs. 20.0±11.2 in group 2 for “General health perception,” 15.2±22.9 vs. 20.0±18.3 for “Incontinence impact,” 19.7±30.6 vs. 6.7±14.9 for “Role limitation,” 15.2±26.3 vs. 13.3±18.3 for “ Physical limitation,” 20.2±32.1 vs. 4.4±9.9 for “Social limitation,” 0.0±0.0 vs. 0.0±0.0 for “Personal relationships,” 5.1±9.1 vs. 0.0±0.0 for “Emotion,” 18.2±20.4 vs. 6.7±9.1 for “Sleep/energy,” and 15.8±7.5 vs. 8.0±8.7 for “Severity measure.” The corresponding KHQ scores in group 2 were lower than those in group 1. As shown in Figure 1, there were statistically significant differences in the scores for “Role limitation” and “Sleep/energy” between 0 week and 6 weeks after KTx in the patients of group 2 treated with solifenacin (P=0.028 and 0.012).

FIGURE 1: Changes in the scores on the King's Health Questionnaire. All scores improved during our study period. In particular, there were statistically significant differences in the scores for “Role limitation” and “Sleep/energy” between 0 and 6 weeks after KTx in the patients treated with solifenacin (P=0.028 and 0.012). KTx, kidney transplantation.

DISCUSSION

KTx has been established as the most suitable treatment option for ESRD. However, the effects of KTx on the urological functions have not yet been clearly elucidated. Few studies have reported on the status of the lower urinary tract, including the bladder and urethra, in patients undergoing KTx. Evaluation of the bladder function before surgery is important in patients undergoing KTx. In particular, it is strongly recommended that patients with clinical symptoms pertaining to the lower urinary tract undergo urodynamic studies before KTx (⁴). A typical form of bladder dysfunction in patients with ESRD under maintenance hemodialysis treatment is the so-called dysfunctionalized bladder, which is characterized by a low capacity and low compliance of the bladder as determined by CM. However, this disorder of the bladder in patients with ESRD is not yet clearly understood. Some researchers have suggested the involvement of atrophic changes of the smooth muscle because of the prolonged oliguria (⁵). It is reported (⁶) that even in patients with long-term dysfunctionalized bladder, urinary dysfunction can be normalized after transplantation with bladder training. Mitsui et al. (⁷) reported that 49% recipients after transplantation in their study had polyuria and 51% had nocturnal polyuria, which affected International Prostate Symptom and KHQ scores though this investigation was carried out with only uroflowmetry and residual urine volume. Moreover, in the case of children, Van der Weide et al. (⁸) reported a high incidence of lower urinary tract syndrome in children with an underlying urological and nephrological disease. They reported later (⁹) that the presence of nocturia can be the result of a high nocturnal urine volume.

In this study, CM revealed a significantly greater increase of the ΔMC after KTx in group 2, with a ΔMC of 173.0±60.7 mL in group 1 vs. 260.1±51.0 mL in group 2 (P=0.005). There was no statistically significant difference in the FS, MC, or compliance between groups 1 and 2. We speculate that the increase of the bladder capacity may not only be due to qualitative changes of the smooth muscle under normal metabolism after complete recovery from the abnormal uremic status but also due to quantitative changes of the sufficient urinary volume. Moreover, the antimuscarinic agent solifenacin also seemed to contribute to the increase of the MC. Some patients in group 2 reported about recurrence of urinary symptoms such as nighttime frequency after stopping solifenacin.

For assessment of the urinary symptoms, a bladder diary may be considered as the gold standard. However, maintaining such a diary can be a burden for the patients and thereby affect compliance with the study (¹⁰). The OABSS is a validated self-assessment questionnaire and consists of four questions about “Daytime frequency,” “Nighttime frequency,” “Urgency,” and “Urgency incontinence” (¹¹). Patients indicate their responses to each question based on the status of the bladder symptoms during the previous week. Therefore, this questionnaire helped us to comprehend the patient's urinary function status in real time. We carried out assessment of the urinary function status using the OABSS at weekly intervals. We defined “abnormal” urinary function parameters as follows: “daytime frequency”: urination eight times or more per daytime; “nighttime frequency”: urination twice or more per night; and “urgency”: occurring once a week or more. In this study, it was indeed remarkable that “urgency” almost disappeared in both groups at 6 weeks after KTx, irrespective of whether the patient was treated with solifenacin or not. This improvement could be attributable to the increase of the bladder capacity. With regard to the high incidence of daytime and nighttime “frequency,” it may be of concern that KTx recipients tend to take a large amount of liquids to avoid dehydration. Even 6 weeks after the surgery, over 80% of patients were embarrassed about “daytime frequency,” and more than half of the patients about “nighttime frequency.” These symptoms affected the patients' daily and social lives, thereby delaying their return to their ordinary lifestyles. To overcome this problem, it is necessary to regulate the intake of liquids according to the patient's postoperative progress.

On the other hand, it may be more important to grasp the perception of physical and mental suffering in the patients; therefore, we evaluated the impact on the health-related quality of life. Among adult KTx recipients, about a half of the patients reported suffering from urinary bother symptoms such as frequency and nocturia during the first year after KTx, and in about two-thirds of these patients, these symptoms were still present 2 to 3 years later (^{12, 13}). Therefore, we can expect urinary problems to exert a marked adverse influence on the QOL of patients undergoing KTx. In this study, the health-related quality of life was evaluated using the KHQ, which consists of questions classified in nine domains “General health perceptions,” “Incontinence impact,” “Role limitation” (restriction of work or house work), “Physical limitation” (restriction of physical activities or travel), “Social limitation” (restriction of social life), “Personal relationships,” “Emotions,” “Sleep/energy,” and “Severity measure.” The answers were graded on a four-point scale (none, 0; slight, 1; moderately, 2; and severe, 3), with the KHQ scores potentially calculated to range from 0 (best health) to 100 (worst health) using the formulae (¹⁴). In our study, the scores in group 2, especially those for “Role limitation,” “Social limitation,” and “Sleep/energy,” were significantly lower than those in group 1 after 6 weeks of solifenacin administration. These superior scores in “Role limitation,” “Social limitation,” and “Sleep/energy” may reflect the complete recovery of “Urgency” and “Nighttime Frequency” as evaluated by the OABSS.

Our investigation also revealed that most patients who underwent KTx suffered from bothersome urinary symptoms, which they felt influenced their QOL. During the first 6 weeks after the operation, both KTx patients who treated and not treated with the antimuscarinic agent consistently showed a higher incidence of such influence than a general Japanese population of subjects older than 40 years (data not shown). In brief, the results were as follows: “Role limitation” (45.5% in group 1 or 20.0% in group 2 vs. 6% in the general Japanese population), “Physical limitation” (36.4% or 40.0% vs. 7%), “Social limitation” (45.5% or 20.0% vs. 4%), “Emotions” (27.3% or 0.0% vs. 10%), and “Sleep/energy” (54.4% or 40.0% vs. 10%) (¹⁵). However, only the prevalence of “Emotion” in group 2 was somewhat close to the data in the general Japanese population, whereas that of group 1 was considerably different. Solifenacin may potentially contribute to a better QOL in patients undergoing KTx. Nowadays, because most KTx recipients can expect favorable long-term prognoses with the remarkable development of excellent immunosuppressive drugs, further investigation of urinary symptoms would be needed for the rapid return of KTx recipients to their usual lifestyles.

CONCLUSIONS

This study demonstrated that patients frequently exhibited bladder dysfunction after KTx, caused by the long-term nonuse of the urinary bladder. To improve the patients' QOL, attention must be paid to the bladder function and urinary symptoms in patients who have just undergone KTx and to consider appropriate treatments. Solifenacin was safe and showed the potential to contribute to improving the QOL of patients undergoing KTx by means of improving the maximum bladder capacity. Anticholinergic drugs may be useful for renal recipients with a very small capacity bladder, who had undergone over 20 years of hemodialysis treatment in Japan.

MATERIALS AND METHODS

All the study procedures were conducted with the approval of the Ethics Committee of Tokyo Women's Medical University. Written informed consent was obtained from each of the patients in our kidney transplant program. Clinical and laboratory information was extracted from the electronic databases and the patients' medical records. The study was performed in accordance with the principles of the Helsinki Declaration.

Patients

Fifty-five patients, including 36 men and 19 women, were examined by video water CM before transplantation (data not shown). Among them, 33 patients (21 men and 12 women; mean age 40.8±12.5 years; and duration of ESRD treatment 69.3±66.4 months) with a MC of less than 200 mL, the criterion for the diagnosis of dysfuncionalized bladder (¹⁶), were enrolled in this study (Table 1). According to the International Continence Society, the bladder function is roughly classified into two phases, the storage function and voiding function. The storage function should be described according to bladder sensation, detrusor activity, bladder compliance, and bladder capacity and the voiding function means detrusor function during voiding (³). The “Defunctionalized” bladder means the bladder has been deprived of some or all of its normal bladder function. In addition, the word “defunctionalized bladder” has been applied to express “small capacity bladder” in previous articles (^17–20). They underwent living-related KTx between July 2007 and August 2009 at our institution; there were no urological complications and the transplanted kidney function after KTx was good though nonstented extravesical ureteroneocystostomy was routinely performed in all patients at our institution.

We divided the 33 patients into two groups by the envelope method. As previously described (²¹), in the present clinical trial, concealment of group allocation was maintained by means of sealed sequentially numbered envelopes, because methods to ensure allocation for a randomized controlled trial in a busy outpatients department may disrupt the usual clinical behavior; group 1 (n=18), consisting of patients who were not treated with any antimuscarinic agent, and group 2 (n=15), consisting of patients who were treated with oral solifenacin at the dose of 5 mg per day. Normal ophthalmic pressure was confirmed by our institute's Ophthalmic Department for all recipient candidates before KTx.

As listed in Table 1, there were no significant differences in the gender, age, the duration of ESRD, type of transplantation, or primary renal disease between the two groups. None of the patients discontinued solifenacin on account of the development of side effects such as thirst, constipation, photosensitivity, or dysuria. None of the patients had any transplant dysfunction caused by solifenacin.

Study Design

The study design is shown in Figure 2. The urinary catheter is normally removed from the bladder 3 or 4 days after the transplant surgery. Thereafter, we examined the patients' bladder function around the time of the operation from two points of view; one from the point of view of determining the quantitative changes of the bladder function and the other from the point of view of assessing the severity of the urinary symptoms. The former was evaluated by CM and the latter by two kinds of questionnaires, OABSS (²²) and the KHQ (¹⁴). CM was performed twice: before and after KTx. The patients were administered these questionnaires weekly after their operation to estimate the urinary QOL (Fig. 1). We analyzed the results of the CM and the two questionnaire surveys. In group 2 patients, solifenacin was continued until the end of the study, that is, until 6 weeks after the transplantation. The primary endpoint in this study was to investigate the urological mechanistic changes brought about by antimuscarinic medications after KTx. The second endpoint was to evaluate the QOL of the recipients after KTx through the adoption of antimuscarinic agents.

FIGURE 2: Study design. We examined the patients' bladder function around the time of the operation from two points of view (1) CM and (2) OABSS and KHQ. CM was performed twice, before and after KTx. The patients were administered these questionnaires weekly after their operation to estimate the urinary QOL. In group 2 patients, solifenacin was continued until the end of this study, that is, until 6 weeks after the transplantation. FK, tacrolimus; MMF, mycophenolate mofetil; MP, methylprednisolone acetate; KTx, kidney transplantation; CM, cystometry; POD, postoperative day; OABSS, Overactive Bladder Symptom Score; KHQ, King's Health Questionnaire; QOL, quality of life.

Video Water CM

CM was performed before and 6 weeks after KTx, to measure the bladder capacity and confirm the voiding function and to determine the presence of any reflux by voiding cystography. The cystography was performed using water, which was instilled through a urethral catheter under fluoroscopic guidance. Bladder capacity was determined at first and maximum voiding desire. Prophylactic antibiotics were routinely administered to all these patients in this study.

Immunosuppressive Regimens

In nonsensitized and blood-type identical recipients, a triple immunosuppressive regimen was adopted. In brief, tacrolimus was used as the calcineurin inhibitor and mycophenolate mofetil as the antimetabolite immunosuppressive drug, as described previously (²³). In all ABO-incompatible and sensitized KTxs, three or four sessions of double-filtration plasmapheresis were undertaken before the surgery to remove anti-blood type and anti-HLA antibodies. Rituximab, an anti-CD20 antibody, was also given at the dose of 200 mg/body for 7 days before the transplantation, as an alternative to splenectomy, to suppress B-cell lineage.

Statistical Analysis

Data were expressed as mean±standard deviation. Statistical comparisons between the two groups were conducted using Student's t test or Mann-Whitney's U test. P values of less than 0.01 were considered as denoting significance in all the tests.

ACKNOWLEDGMENTS

The authors thank the Unit of Radiology of Tokyo Women's Medical University Hospital (S. Kawashima, K. Tanigaki, and Y. Shiratori) for their support for the study. The authors greatly appreciate the cooperation of all the staff members of the Department of Urology, Tokyo Women's Medical University. They also express their deep appreciation to Dr. Ryuji Sakakibara for his appropriate advise.