Myelodysplasia is a group of developmental anomalies resulting from defects that occur during neural tube closure [1]. Myelodysplasia is a complicated disease associated with neurologic, musculoskeletal, and genitourinary system abnormalities [2]. Neurologic lesions may include spina bifida occulta, tethered cord syndrome, meningocele, lipomyelomeningocele, or myelomeningocele [1]. Children born with myelodysplasia have lifelong complex health care needs. Myelodysplasia can result in bladder dysfunction with multiple manifestations, including urinary retention and detrusor underactivity (DU), urinary incontinence, detrusor overactivity (DO), sphincter dysfunction, and recurrent urinary infection, which can potentially lead to progressive renal failure requiring dialysis or transplantation [1].

By combining lower urinary tract dysfunction with grading for upper urinary tract (UUT) damage, including vesicoureteral reflux (VUR), upper urinary tract dilation (UUTD), ureterovesical junction stenosis (UVJS), glomerular filtration rate (GFR) of differential kidney and serum creatinine (Scr) level, Liao developed a new description for all urinary tract dysfunction (AUTD), including the upper and lower urinary tracts in patients with neurogenic bladder (NB) [3-6]. AUTD can comprehensively and objectively assess urinary tract function and guide patients to follow-up regularly to avoid missing items [3-6]. Risk analysis of AUTD can help to differentiate at-risk patients from patients at low risk and develop a neuro-urologic management plan accordingly.

Using the Liao classification for AUTD, we comprehensively evaluated upper and lower urinary tract function of patients with myelodysplasia to determine the risk factors for UUT damage.

Patient characteristics and VUDS findings are summarized in Table 1. Six hundred thirty-seven patients (383 males and 254 females) were included. The average age was 21.51±11.25 years (range, 4–66 years). The average course of lower urinary tract symptoms (LUTS) was 14.08±7.07 years (range, 3–31 years). The proportion of patients who had taken LUTS drugs was 35.01% (n=223). The percentage of patients who had and had not undergone spinal or myelomeningocele closure surgery was 80.85% (n=515) and 19.15% (n=122), respectively. The bladder management methods for patients who have been continuous for >6 months were voluntary micturition (2.04%, 13 of 637), abdominal pressure-assisted urination (83.83%, 534 of 637), intermittent catheterization [IC] (6.75%, 43 of 637), and indwelling urethral catheterization [IDUC] (7.38%, 47 of 637). Among the 637 patients, 171 (26.8%), 41 (6.44%), and 425 (66.72%) were diagnosed with DO, DU, and AcD, respectively, based on VUDS testing.

Of the patients, 28.73% (n=183) had VUR during cystometry on fluoroscopy during VUDS testing. The left, right, and bilateral VUR ratios were 47.54% (n=87), 25.14% (n=46), and 27.32% (n=50), respectively. The distribution of VUR from I–V degrees was 24, 40, 51, 41, and 77, respectively, in 233 ureters. The ratios of low- and high-pressure VUR were 60.94% (n=142) and 39.06% (n=91), respectively. Among 248 patients who underwent MRU, 234 had UUTD (bilateral, n =203; unilateral, n=31). The distribution of UUTD from 1–4 degrees, according to the mentioned [3-6] grading system was 85, 95, 104, and 153, respectively, in 437 ureters.

Ninety-three patients (37.5%) had UVJS with 131 ureters (bilateral, n=38; left, n=25; and right, n=30). A Scr >1.5 mg/dL was demonstrated in 68 of 295 patients, with a mean level of 107.2±81.6 μmoI/L (range, 24–653 μmoI/L). Three hundred thirty-five kidneys from 248 patients had a GFR <50 mL/min (left, n=164; right, n=171). As shown in Table 2, hydronephrosis based on ultrasonography was closely related to ipsilateral VUR (a case of monokidney). Low- or high-pressure VUR had no statistical association with VUR grade (Table 3).

Four hundred twenty-four patients (66.56%) had UUT damage (Table 4). Based on univariate analysis, course of LUTS, bladder sensation, MCC, MDP, BC, PVR, and the bladder management method were shown to be statistically significant factors affecting UUT damage in patients with myelodysplasia (Table 4). Furthermore, we found that the absence of bladder sensation, long-term course of LUTS, decreased MCC and BC, and increased PVR were independent risk factors predicting UUT damage based on logistic regression analysis (Table 5).

In this study we retrospectively analyzed the characteristics of upper and lower urinary tract functions in patients with myelodysplasia. The results were as follows: (1) Hydronephrosis is closely related to ipsilateral VUR. (2) Absence of bladder sensation, long-term course of LUTS, decreased MCC and BC, and increased PVR are risk factors predicting UUT damage.

Urodynamic diagnoses in patients with myelodysplasia are diverse. In this study 66.72% of patients had AcD, 26.84% of patients had DO, and 6.44% of patients had DU. The multiplicity of VUDS diagnoses demonstrated that spinal cord injury is multifocal and the nerve damage may be primarily in the cone. This study also found that long-term LUTS course is an independent risk factor for UUT damage. The above data suggests that all patients with myelodysplasia have lower urinary tract dysfunction, and with the extension of the course of disease, the UUT damage is more serious; however, it needs to be further explained that in China, patients with myelodysplasia undergo neurosurgery early and go to a urology department late, and the lack of attention, correct management of the bladder, long-term regular drug usage and follow-up after surgery lead to UUT damage. So, we recommend that patients with myelodysplasia undergo regular Scr, VUDS and urinary tract ultrasound examinations, and adopt different bladder management plans based on the examination results. If no UUT damage is found, BC is good, bladder capacity is normal, but there are more PVR, IC is recommended; If UUT damage is found, further MRU and nephrogram examinations are required. According to the severity, it is recommended to perform drug therapy combined with IC, or augmentation cystoplasty combined with IC; If severe DO is found and BC is extremely poor, augmentation cystoplasty combined with IC is recommended. All patients are recommended to review regularly the above items every year in order to adjust the treatment and follow-up plan in time to better protect the UUT.

The rate of UUT damage is high and the degree of damage is more severe than traumatic spinal cord injury. Bennett et al. [15] pointed out that IDUC may aggravate urinary tract complications and increase the incidence of UUT damage. Chao et al. [16] did not find a significant difference in creatinine clearance between IDUC and spontaneous voiding. Weld et al. [17] showed that although all bladder management methods help to protect renal function, chronic IDUC may lead to renal deterioration. Dik et al. [18] found that IC for early childhood spina bifida to ensure low pressure in the bladder can protect the UUT to a certain extent. However, in this study, we did not find that a certain type of bladder management is an independent risk factor for UUT damage, which may be caused by the uneven distribution of bladder management data in this study because IC is not popular in China.

Bladder sensation is an important part of urinary function, and can guide the daily urination behavior of healthy individuals. Indeed, individuals with normal bladder sensation can determine when to urinate and can prevent the destructive effects of overdilation of the bladder. Evaluation of bladder sensation during urodynamic studies, which guides daily urinary behavior, is important. Our results showed that the absence of bladder sensation is an independent risk factor for UUT damage. Patients with sensory loss have more urine storage in the bladder, increased bladder capacity and residual urine, and high pressure in the bladder, which may cause VUR and damage the UUT.

UUT damage adversely affects the long-term lives of patients with myelodysplasia. The detrusor contractile function in patients with myelodysplasia is a progressive, pathologic process. In this study the number of patients with DO, DU, and AcD was 26.84%, 6.44%, and 66.72%, respectively. Impaired detrusor contractility is accompanied by increased PVR and MDP, and decreased MCC and BC, resulting in UUT damage. A longterm increase in PVR may cause inflammation of the lower urinary tract and even cause repeated infections. Inflammation and infection of the lower urinary tract can accelerate fibrosis of the bladder wall. Ozkan et al. [19] showed that histologically, severe detrusor fibrosis may be a risk factor for UUT damage. Orellana et al. [20] reported that moderate and severe fibrosis of the detrusor muscle is a risk factor for UUT damage during a full-thickness pathologic biopsy of the bladder wall intra-operatively. Fibrosis of the bladder wall can lead to a decrease in MCC and BC, and an increase in MDP, which can further aggravate fibrosis and increase the workload of the ureter to transport urine to the bladder and damage the vesicoureteral antireflux mechanism. Over time, ureteral function is decompensated, resulting in VUR, ureteral dilation, and hydronephrosis. It has been suggested that a MCC <200 mL is significantly associated with UUT damage [21]. The low BC is associated with UUT damage and is one of the major risk factors [22]. In our study logistic regression analysis indicated that the decrease in bladder volume and BC, and the increase in PVR were independent risk factors for UUT damage. Simforoosh et al. [23] only performed bladder enlargement to improve BC and bladder capacity in patients with a low-compliant bladder after conservative treatment failure, but did not assess VUR. After follow-up, VUR resolved completely in 85.4% of patients.

Protecting UUT function is an extremely important goal in NB patient management. The morphology and innervation of the ureterovesical junction play an important role in the occurrence of VUR, especially in NB patients with a long disease history [24]. A lengthy course of NB and suboptimal bladder management may be the causes of VUR, UUTD, or UUT damage. Reduced BC secondary to progressive fibrosis of the bladder wall is an important factor in the occurrence of VUR. In this study most patients had severe VUR and UUTD. The gradual destruction of the bladder wall causes reduced BC, detrusor fibrosis, and thickening of the detrusor muscle, which often lead to ureteral stenosis in the bladder wall or UVJS, an important factor in the occurrence of UUTD [3-6]. UVJS usually leads to hydronephrosis, ureteric dilatation, tortuosity, adhesions, and renal failure. The sites of obstruction usually begin at the UVJS, and fibrotic cords always form at tortuous points. UUTD and VUR often cause chronic renal failure in NB patients. A patient with UUTD, tortuous knotting ureter and UVJS should undergo ureteral tailoring/shortening and reimplantation during augmentation cystoplasty and renal function could be fully protected. Therefore, evaluation using UUTD and AUTD systems can provide us with objective indicators for the conditions of upper and lower urinary tract function and is also an important part of early guidance and treatment.

There was a significant difference between the presence or absence of VUR and the appearance of hydronephrosis, and the incidence of hydronephrosis was higher in patients with VUR. DeLair et al. [25] conducted a study involving patients with myelodysplasia and found that VUR is an independent risk factor for renal cortex damage. These results suggest that if the patient can manage the bladder in a timely and reasonable manner to prevent or reduce VUR, kidney function may be protected.

In the present study there was no statistical difference in the degree of VUR between low- and high-pressure VUR. We speculate that the antireflux mechanism of the bladder and ureters in patients with myelodysplasia may be damaged, but it is unclear why the left VUR (47.54%) is greater than the right (25.14%) and bilaterally (27.32%); further research is needed to better understand this finding.

The main limitations of this retrospective study were as follows: (1) because some patients were outpatients, UUTD status, GFR, and Scr were not available; (2) most patients had only one VUDS examination in our center, so we did not observe the dynamic changes of urinary tract function.

In conclusion, the current study showed that the UUTD and AUTD systems comprehensively and effectively evaluated the upper and lower urinary tract function of patients with myelodysplasia, and can be used for longitudinal monitoring of urinary tract function of patients without missing items. The current retrospective study using these systems indicates that patients with myelodysplasia have a high incidence of UUT damage. The absence of bladder sensation, long-term course of LUTS, decreased MCC and BC, and increased PVR were independent risk factors predicting UUT damage in patients with myelodysplasia.