Posterior Urethral Valve Treatments and Outcomes in Children Receiving Kidney Transplants

Transcription

1 Posterior Urethral Valve Treatments and Outcomes in Children Receiving Kidney Transplants Matthew S. Fine,* Kenneth M. Smith, Dhirendra Shrivastava, Marie E. Cook and Aseem R. Shukla From the Division of Pediatric Urology, Department of Urology and Division of Pediatric Transplantation, Department of Surgery (MEC), University of Minnesota, Minneapolis, Minnesota Purpose: We evaluated the impact of surgical approaches to posterior urethral valves on renal transplant survival and compared transplant survival in children with vs without posterior urethral valves. Materials and Methods: We reviewed the records of all children who underwent renal transplantation from January 1984 to March 2008 and performed univariate subgroup analysis in those with posterior urethral valves. We evaluated the ureteroneocystotomy method, immunosuppression and valve treatment. In patients with posterior urethral valves we regarded nocturnal and/or daytime incontinence, severe urgency and the need for intermittent catheterization or double voiding for increased post-void residual urine as signs of bladder dysfunction. Results: The initial renal transplant was received by 418 children at a mean age of 5.6 years. The 59 boys with posterior urethral valves received a total of 69 kidneys. By 8-year followup the kidney had failed in 24 of 59 boys with and 143 of 359 without posterior urethral valves (OR , 95% CI , p ). Immunosuppression was consistent in the 2 groups. Outcomes were similar across all ureteroneocystotomy techniques. Initial management for posterior urethral valves was valve ablation alone in 12 boys, vesicostomy in 7 and supravesical diversion in 11. There was no difference in transplant survival or bladder dysfunction based on valve intervention. In 18 boys (55%) we noted overlapping signs of bladder dysfunction, of whom 11 performed intermittent catheterization or had increased post-void residual urine, 4 had severe urgency, 4 had daytime incontinence and 7 had nocturnal incontinence. Bladder dysfunction did not predict increased graft loss (OR 3.306, 95% CI , p ). Conclusions: Of children who undergo renal transplantation boys with posterior urethral valves do not have a higher graft failure rate. Treatment for posterior urethral valves did not significantly impact transplant survival or bladder dysfunction. Abbreviations and Acronyms ESRD end stage renal disease PNT percutaneous nephrostomy tube PUV posterior urethral valve Study received University of Minnesota institutional review board approval. * Correspondence: Division of Pediatric Urology, Department of Urology, University of Minnesota, 420 Delaware St. Southeast, MMC 394, Minneapolis, Minnesota (telephone: ; FAX: ; finex055@ umn.edu). Key Words: urinary bladder, urethra, abnormalities, kidney transplantation, treatment failure POSTERIOR urethral valves occur in 1/4,000 to 1/7,500 boys. 1 They are the most common cause of lower tract obstruction in boys and are often detected during prenatal ultrasound. 2 Before routine prenatal ultrasound approximately a third of patients with PUVs presented at age less than 1 month, a third presented between ages 1 month and 1 year, and a third /11/ /0 Vol. 185, , June 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 2508 POSTERIOR URETHRAL VALVE TREATMENTS AND OUTCOMES OF KIDNEY TRANSPLANTS presented at ages greater than 1 year. 3,4 PUVs can have a profound effect on the bladder and upper urinary tract. Some groups reported that ESRD develops in 13% to 28% of children, requiring dialysis or transplantation. 5 Others reported a 42% rate of ESRD and a 58% rate of chronic renal insufficiency. 2 The 2006 annual report of the North American Pediatric Renal Trials and Collaborative Studies listed obstructive uropathy as the second most common cause for transplantation, accounting for 1,424 of 8,990 transplant cases (15.84%) since The results of renal transplant survival in patients with PUVs who progress to ESRD have been mixed. Several studies show a higher risk of renal transplant loss and increased creatinine in patients with vs without a history of PUVs. 1,7 9 Recent studies revealed no difference in these outcomes Patients thought to be at highest risk for renal transplant loss are those with lower urinary tract dysfunction. 14 It is unclear whether the initial valve intervention in children with PUVs has an effect on the development of bladder dysfunction and subsequent renal graft failure. Our hypothesis was that primary valve ablation alone would lead to higher graft success, perhaps by resulting in less bladder dysfunction compared to that in patients with a nonfunctionalized bladder due to diversion. We evaluated the impact of valve treatment approaches to PUVs on transplant kidney survival, the impact of bladder dysfunction on subsequent renal graft survival and the impact of the valve treatment method on later bladder dysfunction. METHODS Our study was approved by the University of Minnesota institutional review board. We reviewed the records of all pediatric renal transplant patients from January 1984 to March We identified 59 patients with PUVs and created subgroup analysis based on PUV treatment. We evaluated the renal graft survival outcome in all 59 patients and compared this to the outcome in those without PUVs. Information on transplant kidney outcomes, number of times transplanted, renal transplant complications, ureterovesical anastomosis method and immunosuppression protocol were previously reported. 15,16 We identified pretransplant valve intervention in 31 of the 59 PUV cases. We performed 2 data pairings. 1) We used historical groupings of the lower urinary tract or the upper tract in which lower urinary tract interventions included primary valve ablation with or without vesicostomy and upper urinary tract interventions included any supravesical diversion, such as ureterostomy, pyelostomy and PNTs. 2) We analyzed valve ablation alone compared to all forms of diversion. We identified posttransplantation voiding symptoms in 28 patients with known valve intervention and in 33 overall. For study purposes nocturnal and/or daytime incontinence and the need for intermittent catheterization or double voiding due to increased post-void residual urine calculated for age were considered signs of bladder dysfunction. These symptoms were not known to exist in the nonpuv cohort. We also considered urinary urgency and frequency requiring anticholinergics as signs of bladder dysfunction. We compared patients with vs without bladder dysfunction to identify whether pretransplant valve intervention had any effect. We evaluated the outcome on renal graft success against signs of bladder dysfunction. For statistical analysis we used OpenEpi (www. openepi.com). Due to our data limitation we used the Mid-P exact test for nominal variables of small sets. Although our study was limited by df and small numbers, we used chi-square analysis to identify possible subset analysis with the Mid-P exact test. For all modalities statistical significance was considered at p RESULTS A total of 418 children with a mean age of 5.6 years received the initial renal transplant between January 1984 and March The 59 boys who received a total of 68 renal transplants due to PUVs accounted for 14.1% of all those with an initial renal transplant. Average age at initial renal transplantation was 4.9 years (range 0.66 to 17.1) and mean followup was 7.9 years. A total of 359 patients without PUVs received the initial renal transplant at an average age of 5.6 years and had a mean followup of 8.4 years. The renal graft failed in 24 of 59 boys with PUVs and in 143 of 359 children without PUVs for an overall graft survival rate of 59.3% and 60.2%, respectively (OR , 95% CI , p , fig. 1). Ureterovesical anastomosis was performed via the Leadbetter-Politano method in 38 PUV cases, the Lich-Gregoir method in 14, the U-stitch method in 4 and an unknown method in 3. There was no calcu- Figure 1. Renal graft survival at 8 years in patients with vs without PUV.

3 POSTERIOR URETHRAL VALVE TREATMENTS AND OUTCOMES OF KIDNEY TRANSPLANTS 2509 Figure 2. Effect of upper vs lower tract intervention on renal graft outcome. lable difference in outcome with respect to the choice of anastomosis. Three patients with PUVs died, including 1 of cardiac causes and 2 of immunosuppression related nonurinary tract infection. All patients during the study period received the same immunosuppression protocol. 15 PUV intervention type was known in 31 patients, including valve ablation alone in 12, vesicostomy in 7, bilateral cutaneous ureterostomy in 5, bilateral cutaneous pyelostomy in 4 and bilateral PNTs in 3. Two boys had PNTs for longer than 3 months and 1 had PNTs for 14 months while awaiting transplantation. Six boys with valve ablation alone experienced renal graft failure. One boy each with ureterostomy, pyelostomy and PNT had graft failure. All patients with vesicostomy had graft success. The overall graft success rate in those with known valve intervention was 70.1%. When comparing supravesical diversion and ablation with or without vesicostomy, there was no significant difference in graft survival based on valve treatment (OR 1.37, 95% CI , p , fig. 2). However, when we considered vesicostomy as a diversion technique rather than a lower urinary tract intervention, this created a trend toward a worse prognosis for renal graft outcome in patients with valve ablation alone vs urinary diversion (OR 5.013, 95% CI , p ). Voiding dysfunction information was available in 33 boys, of whom 18 (55%) had evidence of bladder dysfunction, including more than 1 symptom complaint in many of them. Many boys had overlapping signs of bladder dysfunction, including intermittent catheterization or increased post-void residual urine in 11, daytime incontinence in 4, nocturnal incontinence in 7, and severe urinary urgency and frequency in 4. When bladder dysfunction was present, we noted a 56% graft failure rate compared to the 27% in those without bladder dysfunction. While bladder dysfunction showed a trend toward increased graft loss, it was not statistically significant (OR 3.306, 95% CI , p ). Voiding dysfunction information was available in 28 boys with known valve intervention. There was no trend toward bladder dysfunction when comparing valve interventions separately (chi-square 3.893, p ). When comparing supravesical diversion and valve ablation with or without vesicostomy, and valve ablation alone vs diversion, there was no significant difference in the development of bladder dysfunction signs (OR 1.949, 95% CI , p and OR , 95% CI , p , respectively). DISCUSSION Our study reinforces that a PUV history does not portend a worse prognosis for renal graft survival compared to that in a nonpuv cohort. Historically this has not always been true. In 1988 Reinberg et al from our institution compared 18 patients with PUV to unmatched controls to evaluate 5-year transplant survival and renal function. 8 Graft survival at 5 years was 50% in those with PUVs while a vesicoureteral reflux group that went on to transplantation had 73% graft survival and a control group with ESRD due to nongenitourinary causes had 75% graft survival. From this they argued that the effects of the valve bladder may explain these findings since in comparison a vesicoureteral reflux bladder did not have these problems and was similar to nongenitourinary causes of renal transplant survival. 8 A contemporary study similarly showed that patients with PUV were at higher risk for graft renal insufficiency but not necessarily for higher renal graft failure. 7 These findings led to speculation about the cause of this discrepancy. Valve bladder syndrome, which is thought to cause this finding, explains the persistent hydroureteronephrosis associated with a noncompliant, thick bladder wall in patients with PUVs as well as the incontinence experienced as a result of increased urine output, decreased bladder compliance and urine stored in the upper tract. 17 Valve bladder is not believed to be a static finding since hypocompliant bladders can eventually decompensate into hypercompliant bladders in the preadolescent years. 18 Periodic urodynamic assessment allows surveillance for that potential decline. Another hypothesis for increased renal graft failure is increased thickness in PUV bladders, leading to more difficult transplant ureteroneocystostomy, and a higher risk of ureteral ischemia, stricture and

4 2510 POSTERIOR URETHRAL VALVE TREATMENTS AND OUTCOMES OF KIDNEY TRANSPLANTS graft failure from obstruction. A recent study showed that children with PUVs who received transplants had a significantly increased incidence of ureteral obstruction on univariate (OR 4.93, p ) and multivariate (point estimate 7.59, p ) analysis. 16 However, ureteral obstruction, stenting and dilation were not significantly associated with increased graft loss or patient death. 16 Recent studies showed no difference in PUV outcomes compared to those in nonpuv cases Indudhara et al reviewed renal transplantation records from May 1968 to November 1988 and found 54% and 41% 10-year survival outcomes in patients with and without a history of PUVs, respectively (p 0.35). 13 Our study adds to this growing literature to support no outcome difference in renal graft survival in those with renal transplantation and with vs without a history of PUVs. A second study point was in regard to the initial surgical approach to PUVs and the effect on the development of bladder dysfunction. The best initial surgical intervention to prevent the bladder and renal consequences of PUVs is unclear. It was hypothesized that the approach to PUVs may have a role in the development of valve bladder syndrome and early valve ablation alone may prevent bladder deterioration and the need for renal transplantation. 17,19 Other studies show that compared to valve ablation alone temporary vesicostomy or supravesical diversion with cutaneous bilateral pyelostomy led to less bladder instability, and better compliance and capacity on urodynamics. 20 Another theory is that renal dysplasia is determined prenatally and cannot be manipulated by postnatal valve intervention. 21 Tietjen et al performed upper tract urinary drainage and renal biopsy in 26 patients with PUVs and persistently increased creatinine, and found that 85% had renal dysplasia. 2 They argued that intrinsic renal dysplastic changes had already occurred in this group and perhaps this explained the high rates of ESRD (42%) and chronic renal insufficiency (56%). 2 Biard et al argued for prenatal approaches to prevent pulmonary hypoplasia and renal dysplasia via vesicoamniotic shunts with favorable results. 22 Salam suggested that there is no difference in outcome between those with prenatal intervention and those with early postnatal intervention. 23 From our findings it appears that while there may be a protective effect of diversion, neither diversion nor primary valve ablation led to bladder dysfunction and renal graft failure. While bladder dysfunction may impact graft failure, we did not find any predictive causes. Studies show that lower urinary tract dysfunction can lead to renal graft failure but case appropriate, customized urological management can decrease this risk, making graft success equal to that in patients with normal bladder function. 24,25 These studies call to attention the role of urodynamic assessment of compliance and capacity before transplantation as an important determination of renal graft success as well as customization to achieve a stable reservoir and reliable drainage. There are several limitations of this study. The retrospective design and academic setting lead to referral and selection biases. Old, incomplete records and temporary loss of pediatric urology at our institution account for the poor percent of known valve interventions in our cohort, that is only 31 of 59 PUV cases (55%). Also, posttransplantation bladder dysfunction data were available on only 33 children. Another limitation is the lack of evaluation of bladder dysfunction in nonpuv transplant cases. However, these patients did not have urological followup. Another limitation is the lack of available urodynamic information on PUV cases. Only a few patients with PUVs had pretransplantation and posttransplantation urodynamic data available. Notwithstanding, our cohort of 31 patients with PUVs with known valve interventions and transplant outcomes is a significant contribution to the literature. Another possible study limitation is the seemingly high 59% to 60% rate of renal graft failure at 8 years. Compared to other series, our graft survival is within the range observed for this followup duration. 10,11 Our cohort included transplants from 1980s and 1990s, and changes in immunotherapy and induction protocols at our institution during this time may account for the lower numbers. 15 In 1987 the mean SD 5-year renal graft survival rate was 79.7% 0.68% for living donor kidneys and 65.1% 0.87% for deceased donor kidneys compared to 1996 to 2005, when 5-year renal graft survival improved to 85.1% 1.03% and 76.9% 1.53, respectively. 6 Our findings pertain to renal transplant survival and not native renal survival. We chose a cohort of patients with transplantation in whom preventing renal deterioration by valve intervention had failed. This study does not elucidate the best initial intervention for PUVs but in our cohort there was no difference in renal transplant survival whether a patient underwent temporary diversion or valve ablation alone. One could argue that in many patients with initial valve ablation alone native renal function was preserved and they did not require transplantation, thus, falling out of our data set, and we selected out the worst of those who underwent primary valve ablation. Previous long-term studies evaluated native renal outcomes and the consensus is that initial primary valve ablation is the best intervention. 3 However, if creatinine and urine chemistry do not respond within 1 week, temporary

5 POSTERIOR URETHRAL VALVE TREATMENTS AND OUTCOMES OF KIDNEY TRANSPLANTS 2511 urinary diversion can be done to relieve urinary tract obstruction and prevent renal deterioration in some cases while significantly increasing the number of surgeries needed. 3 It may be that underlying renal dysplasia causes irreversible injury. There are many future directions that can and should be explored to follow this particularly high risk cohort, including the need for prospective studies of anticholinergic use, clean intermittent catheterization and nocturnal drainage on native and transplant renal function. This study underlines the need for patients with an altered genitourinary tract to undergo continued pediatric urology followup even after successful renal transplantation. Ideally an individualized bladder plan according to patient functional and urodynamic pathology can be used to prevent native and transplant renal function deterioration. CONCLUSIONS Of children who undergo renal transplantation boys with PUV are not at increased risk for graft failure. The initial treatment mode of PUV does not affect ultimate graft survival after transplantation or the rate of bladder dysfunction. The potential for bladder dysfunction and increased renal graft demise in PUV cases underlines the need for continued longterm pediatric urology followup, and individualized intervention and management. REFERENCES 1. Bartsch L, Sarwal M, Orlandi P et al: Limited surgical interventions in children with posterior urethral valves can lead to better outcomes following renal transplantation. Pediatr Transplantation 2002; 6: Tietjen DN, Gloor J and Husmann DA: Proximal urinary diversion in the management of posterior urethral valves: is it necessary? J Urol 1997; 158: Smith GH, Canning DA, Schulman SL et al: The long-term outcome of posterior urethral valves treated with primary valve ablation and observation. 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