Early Start to Therapy Preserves Kidney Function in Spina Bifida Patients

Transcription

1 european urology 49 (2006) available at journal homepage: Pediatric Urology Early Start to Therapy Preserves Kidney Function in Spina Bifida Patients Pieter Dik, Aart J. Klijn, Jan D. van Gool, Catherine C.E. de Jong-de Vos van Steenwijk, Tom P.V.M. de Jong * Paediatric Renal Centre, Wilhelmina Children s Hospital, University Medical Centre, Utrecht, The Netherlands Article info Article history: Accepted December 30, 2005 Published online ahead of print on January 19, 2006 Keywords: Spina bifida Urinary continence Renal function Intermittent catheterisation Urodynamic study Bladder pressure Abstract Objective: Renal scarring and renal failure remain life-threatening for children born with spinal dysraphism. We reviewed our data of spina bifida patients to evaluate whether optimal treatment of the neurogenic bladder from birth onwards can preserve kidney function. Methods: We reviewed data on all newborns with spinal dysraphism who were referred to our hospital between January 1988 and June We looked at their situations at referral and at follow-up: the type of treatment, antimuscarinic agents, clean intermittent catheterisation (CIC), antibiotic prophylaxis, and operations (sling procedures, bladder augmentations, antireflux procedures). Renal function (ultrasound, DMSA scan, serum creatinin, creatinin clearance) and bladder function (urodynamic studies) were evaluated over time. Results: Data of 144 children of 176 could be evaluated by the end of the study: 5 patients had pre-existing renal abnormalities, 69 had an overactive sphincter, 27 had reflux, and six had renal scarring. None are currently developing end-stage renal disease. All patients with spina bifida aperta started CIC and antimuscarinic therapy shortly after birth. Five of the six patients with renal scarring were started on therapy with intermittent catheterisation and antimuscarinic therapy several months after birth. Sixty-three of 82 children with spina bifida were dry at school age (age six), although 37 of these had not had an operation. Conclusion: We show that an early start to therapy helps to safeguard renal function for children born with spina bifida. Our data support other recent reports that children born with spina bifida can probably use their own kidneys for a lifetime, if they are given adequate urological treatment. To protect the upper urinary tract, we need to ensure low intravesical pressure by starting children early on CIC (the preferred treatment); antimuscarinic agents to counteract detrusor instability are indispensable in most cases. Proactive treatment of risks for upper tract deterioration results in a negligible loss of renal function, even when early urinary continence is included in the treatment protocol. # 2006 Elsevier B.V. All rights reserved. * Corresponding author. Paediatric Renal Centre, Wilhelmina Children s Hospital, UMC Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands. Tel ; Fax: address: prc@azu.nl (T.P.V.M. De Jong) /$ see back matter # 2006 Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 49 (2006) Introduction The prevalence of children born with spina bifida in The Netherlands is 0.38 per 1,000 live births [1]. Though the survival rates for babies born with spina bifida have improved enormously [2], renal failure is still widely accepted and reported as a long-term complication and remains a major cause of death, often before adulthood [3 6]. Little et al. [7] reported a series of kidney transplants in children with spina bifida. This illustrates the real possibility that these patients will develop end-stage renal failure. The incomplete innervation of the urinary bladder and pelvic sphincter caused by the neural tube closing defect can cause problems in the bladder s storage and emptying functions, and lead to high intravesical pressures, which can in time cause renal damage or failure [8,9]. Vesico-ureteral reflux (VUR) and recurrent pyelonephritis are major causes of renal failure in early and later life [10 12], whereas complications from urinary tract infections occur especially in the first year of life [13]. Bladder outlet obstruction causes uropathy, which, if left untreated, will in time cause renal damage, especially in the case of VUR. We reviewed data on our spina bifida patients to evaluate whether adequate preventive measures and early treatment of complications can help to optimise bladder function and preserve kidney function. 2. Methods Starting in January 1988, all new spina bifida patients who presented at our hospital were initially treated with clean intermittent catheterisation (CIC), antimuscarinic agents, and antibiotic chemoprophylaxis from birth onwards to prevent obstructive uropathy and preserve renal function. Antimuscarinic agents such as oxybutynin were administered to ensure low intravesical pressure. Urodynamic studies (UDS) were conducted to evaluate the effects on bladder function, and treatment was tailored individually over time, if possible. From January 1988 until June 2001, 176 children with spina bifida were referred to our hospital. Kidney development and lower urinary tract function were monitored. At first presentation an ultrasound of the urinary tract was made and the serum creatinin level was measured. All the patients attended the spina bifida outpatient clinic at regular intervals and underwent monitoring by several specialists. UDS were done at the age of 3 4 months and then at yearly checkups. Standard five-channel urodynamic tests were conducted, with an emphasis on detrusor overactivity, filling pressures, and leak point pressures. Pressures of more than 40 cm of water were considered a risk for the upper urinary tract [14]. Urinary tract problems at intervening times were treated in the paediatric urology outpatient clinic. Surgery for urinary incontinence was offered in most cases before the child started school (age six) to enable the child to stay dry during the day. Surgeries for VUR, recurrent infections, and high detrusor pressures were performed if necessary. Female wheelchair patients who needed to be transferred from the wheelchair for each catheterisation were offered a continent catheterisable stoma. For this study, we evaluated the results of ultrasound scans to detect renal parenchymal scarring and recorded overall kidney function from serum creatinin levels. We looked for parenchymal scars, dilatation, difference in kidney length, and other signs of renal damage. If the ultrasound results gave rise to doubts, we did DMSA scans to further evaluate patients who were suspected to have scarring. A DMSA scan was also done when an ultrasound of the kidneys was not reliable (for patients with positional anomalies or major scoliosis). If we suspected renal anomalies, we used Schwartz s formula to calculate the creatinin clearance: creatinin clearance in ml=min body length ¼ k creatinin mmol=l: serum We used a value of k = 38 for boys and girls. We studied continence and dryness in two groups of patients (operated and nonoperated) and divided our data into two groups (children with spina bifida aperta and those with spina bifida occulta); only a few of the differences will be discussed here. 3. Results Of 176 children, 25 newborns died for reasons that were unrelated to the urinary tract. Three of these, however, had renal abnormalities: one had left kidney dilatation and two had no left kidney. Seven children were lost to follow-up because they moved to another city or hospital. Of the 144 remaining patients, 70 were boys (49%) and 74 (51%) were girls. Thirty-five patients (24.3%) had a spina bifida occulta; 109 (75.7%) a spina bifida aperta. The follow-up periods ranged from 5.4 to months (mean 81.6 months). None of the children had an abnormal serum creatinin value shortly after first presentation Ultrasound and cystography at presentation Results of early ultrasound investigation of the kidneys are summarised in Table 1. Five renal units were slightly dilated (three unilateral and two bilateral) and four units showed gross dilatation (grade 4 5 reflux in four patients who were referred to our institution at an older age [>6 months] but who had been untreated until then). One patient showed a multicystic dysplastic left kidney and another had no right kidney. One patient had a horseshoe kidney and two others had an upper pole cyst.

3 910 european urology 49 (2006) Table 1 Ultrasound findings in 144 spina bifida patients at first presentation and at follow-up (286 functioning kidneys) DMSA scar or function loss Suspicion of renal scarring Double system Horseshoe kidney Upper pole cyst MCKD or aplastic Gross dilatation unilateral Minimal dilatation bilateral Minimal dilatation unilateral n = 144 Normal kidneys Ultrasound at first presentation Ultrasound during follow-up Renal damage was confirmed with DMSA scan in 6 patients Ultrasound and cystography during follow-up During follow-up we found some dilatation in 10 renal units in seven patients: three patients had minimal bilateral dilatation and four had a minimal unilateral dilated kidney. One patient had more severe unilateral dilatation. Six children currently have grade 1 2 VUR. One girl had grade 4 bilateral VUR and had a bilateral ureteral reimplantation, combined with a detrusorectomy after our study was completed. One girl later had a left ureteric obstruction caused by an orthopaedic surgical complication. After reanastomosis of the obstructed ureter, a DMSA scan showed left side renal function of 20%. Unilateral parenchymal scars were suspected in 10 patients on ultrasound, but this was confirmed in only six (all girls) by DMSA renal scan (see Table 1) DMSA study DMSA scintigraphy was performed in patients we suspected of having renal damage based on their ultrasounds. Two patients had 30% and 34% function, respectively, in their right kidneys. Four showed poor remaining function (16%, 17%, 20%, and 21%) in their left kidneys. The parents of the girl with 16% function admitted that they did not always comply with the catheter regime. A vesicovaginal fistula was made and ureteric re-implantation was done in the girl with the 17% left kidney. Her parents refused a bladder augmentation operation and did not comply with the catheter regime. The loss of kidney function in the girl with 20% was caused by an obstruction from an orthopaedic surgery complication. Two patients had a pre-existing parenchymal lesion: one boy had a left multicystic dysplastic kidney and a girl had a small dysplastic right kidney. In the total of 144 patients (286 functioning kidneys), six kidneys showed parenchymal damage. Three patients had dilating reflux and started CIC and antimuscarinic therapy when they were older than six months. Regarding the occurrence of renal scarring, we reviewed patients over the past four years (extra follow-up): one patient with a previously known renal scar had further renal deterioration Urodynamic study We experienced few difficulties in performing UDS in this group of patients. They were used to catheterisation, and insertion of the measurement catheters has never been a problem. Sedation was

4 european urology 49 (2006) Table 2 Detrusor and sphincter behaviour in 144 patients with neurogenic bladder 144 patients with spina bifida (70 boys, 74 girls) Inactive Detrusor Active Sphincter Inactive VUR 21 4VUR 2 with renal scarring 1 with renal scarring Active 29 4 VUR 40 8VUR 1 with renal scarring 2 with renal scarring not necessary. In most of the cases a perfect registration was possible. The results of our urodynamic studies are summarised in Table 2. Overactivity of the sphincter was found in 69/144 patients, and overactivity of the detrusor in 61/144 (Table 2). VUR was seen in children with spina bifida aperta and occulta and occurred in 27 patients (12 of these had an overactive sphincter, and three eventually showed loss of renal function). However, even in those with inactive sphincters, 15 patients had VUR (three had dilating reflux and renal function loss on DMSA). More incontinence is seen in spina bifida aperta patients than with occulta patients. Our definition of dry is when a patient is on catheterisation but does not require pads. Of the 82 patients older than six, most were dry and on CIC with or without an operation. Thirty-four patients were operated (bladder augmentation with or without sling procedure (depending on urodynamic findings). After this operation, two patients remained incontinent, 26 became dry, and six still needed pads. The overall results of dry or incontinent six-yearold patients are summarised in Table 3: 63 patients were dry (49 on CIC and 14 with spontaneous micturation and continence), nine used pads, and 10 were still incontinent Follow-up creatinin level The follow-up creatinin levels of 103 children were recorded. The case histories, renal ultrasounds, and clinical and urodynamic follow-ups of the other 41 patients gave no reason to suspect renal deterioration. We used Schwartz s formula Table 3 Eighty-two patients with spina bifida, older than six (school age) Incontinence in 82 spina bifida patients >6 years Without operation After operation Total Dry Pads Incontinent Ten were still incontinent, four still need to receive a sling and augmentation plasty. to calculate the creatinin clearances. Of the 103 children, two had a creatinin clearance (Ccr) of less than 80 ml/min. One girl had a Ccr of 54 ml/min, but she is very short (height less than 2.5 times the standard deviation under normal). She is currently five years old and has a normal UDS with no signs of VUR. Another girl has a Ccr of 70 ml/min and her left ureter was reimplanted because of grade 5 left VUR; she currently has no VUR, but a DMSA scan showed a left kidney function of 17%, as had been suspected from the ultrasound. A girl with a preexisting right renal scar had a calculated Ccr of 84 ml/min. The other 98 patients had a Ccr well above 80 ml/min (mean 133 ml/min) Antimuscarinic medication and catheterisation Antimuscarinic drugs are still being used by 94/144 patients (65.3%), with an equal male to female ratio. Intermittent catheterisation was eventually stopped in 22 patients (15.3%), because repeated UDS results were almost normal Surgery The ureter was reimplanted into the bladder (five bilaterally) in 14 girls and a left ureteral reimplantation was done in one boy. To provide social urinary continence and to improve bladder compliance, an auto-augmentation of the bladder was performed in 37 patients (detrusorectomy), and combined with a sling procedure in 22 of these [14]. 4. Discussion Uropathy causes bladder outlet obstruction which, if left untreated, will in time cause renal damage. The rationale for protecting the upper urinary tract therefore lies in controlling both bladder functions: (1) ensuring safe intravesical pressures during urine storage, and (2) establishing adequate emptying of the bladder at low pressures. Lapides et al. [15] postulated as early as 1972 that maintenance of a good blood supply to the renal pelvis, ureter,

5 912 european urology 49 (2006) bladder and urethra by avoiding high intraluminal pressures and over-distension is the key to prevention of urinary tract infection. To prevent complications from obstructive uropathy, CIC should be started shortly after presentation, in most cases combined with oxybutynin to prevent high intravesical pressures [16 18]. Not all patients with a spina bifida will develop neurogenic lower urinary tract dysfunction, which leads to detrusor-sphincter dyssynergia [9]. Predicting later detrusor and pelvic floor behaviour in a newborn child with spina bifida is impossible. We firmly consider that CIC and antimuscarinic agents should be started as early as possible and to decide later, based on UDS findings, which therapeutic strategy is best for an individual patient. We found that parents and patients accepted CIC very well. Parents were taught how to catheterise their newborn starting one week after closure of the spinal defect. Treatment was tailored individually over time, if possible. If there was detrusor overactivity, antimuscarinic agents were continued and, if the sphincter was overactive, CIC was continued. The calculated Ccr for all our patients showed that even the six with renal scarring still have normal renal function. However, using Schwartz s formula for Ccr calculations has its limitations: children with spina bifida have less body mass, less muscle mass, and they are smaller than normal children. Moreover, serum creatinin will be normal as long as the contralateral kidney function is intact (even down to 20% function). We doubt whether Ccr adequately reflects kidney function in spina bifida follow-up. However, a recent report [19] regards even simple serum creatinin as a good choice for frequent evaluation of renal function in children with a neuropathic bladder. In our group of 144 patients, six had unilateral scarring and partial loss of function in a total of 286 functioning kidneys (2.1% of the kidneys were affected). One of the six patients had not received antimuscarinic medication or intermittent catheterisation even though they had VUR grade 4 5. Three of the six had late onset of treatment because the occult spina bifida was recognised later and they were only referred at a later stage. In our experience many problems of occulta patients were underestimated. Most were started on antimuscarinica and CIC only after four to six months after birth. The greatest percentage of renal deterioration was observed in the occulta group. Starting therapy as early as possible is essential if renal damage is to be prevented. We had no control cohort, but a study by Woodhouse [6] of such patients who had received little treatment showed that the incidence of total renal failure before puberty was 18%, with 30% after puberty. A low percentage (1.2%) of renal function deterioration was reported by Hopps and Kropp [20] in a retrospective study of 83 patients who could be evaluated from a total of 188: they were all high risk patients (retention and hydronephrosis) and had been treated with incontinent vesicostomy or CIC. There was no attempt to preserve compliant bladder reservoirs or to achieve continence, in contrast to our series of patients. Remarkably, 29 of the 65 initially low risk patients later became high risk at a mean age of 3.1 years; proper action was taken only after an episode of pyelonephritis or other complication. We strongly recommend a more proactive attitude to prevent any possible urological problems in children with spina bifida. Follow-up with ultrasound scans of the kidneys is a reliable monitoring method, and our data support those of other authors [21,22]. Spina bifida patients do not necessarily need to be subjected to DMSA scans if serum creatinin and ultrasound scans are normal, especially if UDS show low bladder pressure. Interestingly, the chance of renal failure increases with age. In the past, cortical damage has been described in 13.3% of children with spina bifida under the age of two; 27.3% of spina bifida patients older than 10 have renal parenchymal damage [23]. Muller et al. [24] reported evidence of renal damage in up to 40% of patients, but other recent studies have not provided exact data on the progression to ESRD (end-stage renal disease) in patients with spina bifida. The importance of continuous followup of patients with spina bifida by a multidisciplinary team has already been stressed by several studies [5,25 28]. Patients and parents can see all the specialists in one day, although they may not need to see them all at each check-up. They may even be dismissed from monitoring by certain specialists. However, we strongly stress the importance of continuing urological follow-up, even well into adult life, since renal or bladder function can still deteriorate during adolescence. 5. Conclusions Children born with spina bifida can probably use their own kidneys for a lifetime if they start to receive adequate early urological treatment soon after birth. To protect the upper urinary tract, ensuring low intravesical pressures is necessary; therefore, an early start to therapy is essential to prevent renal damage. Continuation of intermittent

6 european urology 49 (2006) catheterisation, whether combined with antimuscarinic agents or not, should be based on repeated urodynamic studies. Long-term follow-up is necessary since renal or bladder function can still deteriorate after childhood. Preservation of renal function and treatment of urinary incontinence should be end targets. Proactive treatment of risks for upper tract deterioration results in a negligible loss of renal function, even when early urinary continence is included in the treatment protocol. Acknowledgements The support of S.H. de Vries and J.L. Senior-Rogers is gratefully acknowledged. Funding: None. Conflict of interest statement: We declare we have no conflict of interest. References [1] Pal-de Bruin KM, Buitendijk SE, Hirasing RA, den Ouden AL. Prevalence of neural tube defects in births before and after promotion of periconceptional folic acid supplementation. Ned Tijdschr Geneeskd 2000;144: [2] Wen SW, Liu S, Joseph KS, Rouleau J, Allen A. 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