Setting the Speed Limit: A Pilot Study of the Rate of Serum Creatinine Decrease After Endoscopic Valve Ablation in Neonates

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1 Setting the Speed Limit: A Pilot Study of the Rate of Serum Creatinine Decrease After Endoscopic Valve Ablation in Neonates A. V. Deshpande, B. S. Alsaywid and G. H. H. Smith* From the Department of Urology and Centre for Kidney Research (AVD), Children s Hospital at Westmead and University of Sydney, Sydney, New South Wales, Australia Purpose: In neonates with a posterior urethral valve serum creatinine is increased. It decreases after successful relief of obstruction. Clinicians consider urinary diversion if serum creatinine remains increased. However, the optimal rate of decrease of serum creatinine is not defined. We generated useful data on the rate of serum creatinine decrease in neonates with a posterior urethral valve by introducing the idea of a prediction curve. Materials and Methods: We reviewed the medical charts of 15 consecutive children treated for a posterior urethral valve in the neonatal period at our institute between 2002 and The 11 children with a delayed diagnosis of a posterior urethral valve were excluded from analysis. Serial serum creatinine levels in the cohort of 15 patients were analyzed to estimate 1) the rate of decrease after valve ablation and 2) the time needed to achieve a nadir. Results: One child died of renal insufficiency on day 10 of life and was excluded from study. Serum creatinine attained a nadir at about age 6 months but 73% of the total decrease occurred within the first 2 months of life, which was also equal to a 45% decrease from the peak values recorded soon after birth. The rate of decrease did not appear to be influenced by the peak values. Children with normal peak creatinine or intercurrent problems did not follow the trend. Conclusions: The rate of decrease in serum creatinine in the first few months of life may provide useful information on the adequacy of valve ablation. Study received human research ethics committee approval. * Correspondence: Department of Urology, Children s Hospital at Westmead, Locked Bag 4001, Corner Hainsworth St. and Hawkesbury Rd., Westmead, 2145, New South Wales, Australia (telephone: ; FAX: ; Grahames@chw.edu.au). Key Words: kidney, abnormalities, creatinine, reference values, infant POSTERIOR urethral valves are responsible for significant long-term nephrourological morbidity. Effective treatment in infancy may minimize the risk of future renal insufficiency. 1 In neonates with a posterior urethral valve serum creatinine is increased. It decreases after successful relief of obstruction. Endoscopic ablation of a posterior urethral valve is the current gold standard of therapy. 2 4 Clinicians consider higher diversion if serum creatinine does not decrease from the increased level or hydronephrosis does not improve. However, there is a paucity of data on the optimal rate of decrease in serum creatinine after endoscopic valve ablation. In fact, even the month-to-month changes in serum creatinine in normal infants are poorly documented. We plotted the serial decrease in serum creatinine in a small cohort of neonates after endoscopic ablation of a posterior urethral valve with the aim of introducing a prediction curve, which may evolve into a useful clinical guideline to assess the adequacy of treatment. METHODS This study is a retrospective medical record review. Consent was obtained from /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 2498 SERUM CREATININE DECREASE AFTER ENDOSCOPIC VALVE ABLATION IN NEONATES the human research ethics committee to access the medical records of all patients with a posterior urethral valve. All neonates treated for a posterior urethral valve after detection of prenatal hydronephrosis from January 2002 to December 2007 were included in the study. All patients underwent endoscopic ablation of a posterior urethral valve by the team of one of us (GHHS) after stabilization. They were admitted to the neonatal intensive care unit for fluid and electrolyte management, and treatment of associated pulmonary complications as necessary. Fluid and salt requirements were carefully titrated in each patient, and the optimal hydration and electrolyte balance was achieved in all before surgical treatment. All patients were assessed by renal ultrasound and voiding cystourethrogram to confirm the diagnosis of a urethral valve. Surgical Treatment Our policy was to incise the valve at the 5, 7 and 12 o clock positions using a 9Fr Wolfe resectoscope and cutting current. The end point of primary ablation was determined by visual assessment of destruction of the valve leaflets. An indwelling catheter (feeding tube) was left in place for 48 hours after valve ablation. Patients were discharged home on oral antibiotics and voiding cystourethrogram was repeated 6 weeks after valve ablation. Cystoscopy was done with further ablation if there was significant posterior urethral dilatation, as guided by the ratio of the posterior urethral diameter to the distal urethral diameter. 5 Data Collection Demographic and prenatal data were collected. Growth charts were reviewed and the z score (observed minus expected value/sd) for height (length) was recorded at 3-month intervals. Serial serum creatinine levels were recorded. Mean serum creatinine in the group was reported at 3, 5 and 7 days, at 2 and 4 weeks, and at 2 to 8 and 12 months. We excluded serum creatinine levels on day 1 of life from analysis since they reflected maternal creatinine. In case of missing values a weighted mean of the previous and next values was calculated to estimate the missing value and facilitate graphical representation. Analysis Mean 1 SD serum creatinine was plotted. The mean decrease in serum creatinine at 2 months, and its relationship to mean peak and nadir values was estimated. Nadir serum creatinine in a given patient was defined as the lowest serum creatinine during year 1 of life. Mean time to the nadir was estimated. To explore whether the rate of decrease of serum creatinine was different in children with high nadir serum creatinine, ie those at a higher risk for renal insufficiency, we identified those in whom nadir creatinine was above the normal range of 20 to 45 mol/l. We plotted the rate of decrease of serum creatinine in these patients separately and compared that to the rate in the remainder. RESULTS Of the 26 children with a posterior urethral valve treated at our institution between 2002 and 2007, 15 neonates were included in the study. One neonate who died of renal insufficiency on day 10 of life was subsequently excluded from analysis. Median age at diagnosis in the other excluded patients was 3 months (range 2 months to 4.5 years). Prenatal records were available for 12 of the 15 patients. All presented with bilateral hydronephrosis with abnormal echogenicity (a total of 8 kidneys in 5 patients) and poor corticomedullary differentiation on prenatal ultrasound. The prenatal diagnosis was made at a median of 29 weeks of gestation (range 16 to 32). Four pregnancies were complicated by oligohydramnios, including 1 with anhydramnios, and pneumothorax developed in 3 neonates soon after birth. Two patients were mechanically ventilated. The patients presented after a prenatal diagnosis and usually with maternal serum creatinine measurement, normal electrolytes and no infection. However, creatinine usually increased after day 1 of life, before confirmation of the diagnosis and before treatment. In 1 patient serum creatinine remained in the normal range, including 43 mol/l on day 5 of life (see table). All patients were catheterized with a feeding tube while awaiting valve ablation. As part of metabolic stabilization and fluid resuscitation, 4 patients received double maintenance fluids and 10 received sodium bicarbonate supplementation. Two patients received potassium supplements and 2 received diet caloric supplements. The neonate who died was born with bilateral hydroureteronephrosis and Potter s facies, and acute renal failure developed soon after birth. High urinary diversion (ureterostomy) was performed but the neonate died on day 10 and was excluded from further analysis. The other 14 patients underwent endoscopic valve ablation between days 2 and 27 of life (median 7). One patient with bilateral prenatal hydronephrosis and oligohydramnios was reported to have normal voiding cystourethrogram on day 2 of life. Subsequently on day 10 of life repeat voiding cystourethrogram suggested posterior urethral valves and he underwent high diversion with percutaneous nephrostomy. After transfer to our unit he underwent cystoscopic valve ablation on day 27. We included him in analysis since he met study inclusion criteria. Four patients underwent further cystoscopy, ie endoscopic ablation Serum creatinine in 14 newborns after endoscopic ablation of posterior urethral valves Age Mean SD Serum Creatinine (range) ( mol/l) 3 Days (44 266) 5 Days (43 313) 1 Mo (39 248) 2 Mos (36 200)* 6 Mos (35 86) 12 Mos (29 140) * Mean decreases 45% from high value and 73% as proportion of decrease to nadir.

3 SERUM CREATININE DECREASE AFTER ENDOSCOPIC VALVE ABLATION IN NEONATES 2499 of residual valve leaflets between ages 6 weeks and 6 months (median 15.5 weeks). This did not appear to result in a more rapid serum creatinine decrease compared to that in patients who did not require further intervention. There were no surgical complications. Upper tract dilatation improved in all patients. After hospital discharge all patients were closely followed and received salt supplementation and nutritional advice as part of nephrology care. The median z score (observed minus expected value/sd) for height at 1 month was 1.2 in 7 patients, which improved to 0.14 in 6 at 3 months, to 0.4 in 5 at 6 months and to 0.2 in 5 at 12 months. Serial creatinine measurements were available in all 14 patients until age 6 months. Four values that were missing between ages 6 to 12 months were estimated using the weighted mean of the values immediately before and after the missing values. Graphic representation of mean values showed a brisk decrease in serum creatinine between 5 days and 2 months of life (fig. 1). Mean serum creatinine was highest on day 5 of life. The decrease in mean serum creatinine at age 2 months was about 45% from the peak (see table). Nadir creatinine was attained around age 6 months (range 3 to 8) in 8 of the 14 patients. Of the total eventual decrease of mean peak value to mean nadir value 73% was seen by age 2 months (see table). When the trend of the serum creatinine decrease in patients with abnormal nadir creatinine was graphically compared to that in patients with a normal nadir, the rates of decrease appeared similar (fig. 2). One patient with high nadir creatinine presented with pyelonephritis at age 3 months (serum creatinine 306 mmol/l). This was responsible for the second peak in the corresponding line in the graph (fig. 2). One patient did not follow the trend described. He had a peak serum creatinine of 44 mol/l (normal 20 to 45). The total decrease at age 2 months in this patient was 18%. Serum creatinine umol/l Age in days laboratory upper limit of normal nadir creatinine in normal range high nadir creatinine Figure 2. Mean serum creatinine decrease in 5 patients with higher nadir of greater than 45 mol/l (green curve) and 9 with normal nadir of less than 45 mol/l (red curve). Dotted line indicates upper limit of normal. DISCUSSION Endoscopic ablation of a posterior urethral valve is the current gold standard of treatment in neonates with a posterior urethral valve. 2 4 The need for high diversion has been questioned in the recent literature. 6 8 Nevertheless, proponents of high diversion suggest that it may become necessary in rare situations in which serum creatinine remains increased due to secondary vesicoureteral junction obstruction. We do not support higher diversion in children with a posterior urethral valve since we have only seen persistent vesicoureteral junction obstruction after ureteral reimplantation in this group. All except 1 patient in this small series underwent uneventful therapeutic valve ablation and showed optimal improvement in anatomical and laboratory indicators of renal function. Objective measurement of the adequacy of endoscopic ablation of a posterior urethral valve in neonates would be useful in practice. Objective mea Mean serum creatinine in umol/l Age in days Figure 1. Mean 1 SD serum creatinine decrease after endoscopic ablation of posterior urethral valve, excluding levels on day 1 of life

4 2500 SERUM CREATININE DECREASE AFTER ENDOSCOPIC VALVE ABLATION IN NEONATES surements of upper tract dilatation on ultrasound are easily influenced by hydration and bladder fullness in this age group. These results are also performer dependent. Hence, serum creatinine continues to be a commonly used surrogate marker for relief of obstruction and consequent improvement in renal function in infants with a posterior urethral valve. Sparse data are available that allow a clinician to assess whether short-term changes in serum creatinine are optimal. This would be especially useful in the setting of equivocal radiological evidence. We believe that introducing the idea of a prediction curve of the decrease in serum creatinine with a signpost at age 2 months would be beneficial. Most clinicians decide on the need for further intervention around that time. Our data suggest that a predicted decrease of 45% in serum creatinine from the peak value would be a good indicator of optimal treatment at age 2 months. The possible mechanisms responsible for the rapid decrease in serum creatinine in the first 2 months after valve ablation in neonates have been poorly studied. Relief of chronic obstruction is the most obvious explanation. Other mechanisms, such as ongoing maturation of nephrons, resulting in an improved glomerular filtration rate, may also contribute. Children with obstructive uropathy are offered salt supplementation since they are prone to transient pseudohypoaldosteronism. 9,10 This may also result in improved renal blood flow and decreased serum creatinine in these patients. The assessment of the precise role of each of these factors is beyond the scope of this study. The true significance of nadir serum creatinine is uncertain in modern treatment pathways. 1 As mentioned, nadir creatinine in year 1 of life was suggested as a predictor of eventual end stage renal disease As also suggested by Denes et al, 15 we believe that it would be useful to obtain an early, accurate estimate of what nadir creatinine will be. Our data suggest that the decrease in serum creatinine at age 2 months is 73% of the total decrease to nadir creatinine. After confirmation by more data this may allow earlier assessment of the adequacy of treatment and prognosis. CONCLUSIONS This is a small, retrospective study. Our results are characterized by wide SDs and, hence, a lack of precision. Nevertheless, this study introduces the idea of a prediction curve and generates useful data estimates of the expected rate of the serum creatinine decrease after successful endoscopic ablation of a posterior urethral valve. Our results must be validated in larger, longer term studies but may then add to prognostic ability and clinical decision making in infants with a posterior urethral valve. This will also provide a platform for objective comparison between the efficacy of endoscopic valve ablation and higher diversion in restoring renal function in neonates with a posterior urethral valve. ACKNOWLEDGMENTS Dr. Elisabeth Hodson, Department of Nephrology, Children s Hospital at Westmead, provided guidance for the manuscript. REFERENCES 1. Kousidis G, Thomas DF, Morgan H et al: The long-term outcome of prenatally detected a posterior urethral valve: a 10 to 23-year follow-up study. BJU Int 2008; 102: Chen WH, Lai MK, Lin GJ et al: Clinical experience of a posterior urethral valve. J Formosan Med Assoc 1994; 93: Gupta SD, Khatun AA, Islam AI et al: Outcome of endoscopic fulguration of a posterior urethral valve in children. Mymensingh Med J 2009; 18: Warren J, Pike JG and Leonard MP: A posterior urethral valve in Eastern Ontario - a 30 year perspective. Canad J Urol 2004; 11: Bani HO, Prelog K and Smith GH: A method to assess posterior urethral valve ablation. J Urol 2006; 176: Ghali AM, El Malki T, Sheir KZ et al: A posterior urethral valve with persistent high serum creatinine: the value of percutaneous nephrostomy. J Urol 2000; 164: Smith GH, Canning DA, Schulman SL et al: The long-term outcome of a posterior urethral valve treated with primary valve ablation and observation. J Urol 1996; 155: Tietjen DN, Gloor JM and Husmann DA: Proximal urinary diversion in the management of a posterior urethral valve: is it necessary? J Urol 1997; 158: Bulchmann G, Schuster T, Heger A et al: Transient pseudohypoaldosteronism secondary to a posterior urethral valve a case report and review of the literature. Eur J Pediatr Surg 2001; 11: Parisi G, Rojo S, De Pascale S et al: Transient pseudohypoaldosteronism secondary to congenital malformation pathology of the urinary tract (valves of the posterior urethra): a report of a case with elements of a physiopathological nature. Pediatr Med Chir 1920; 4: DeFoor W, Clark C, Jackson E et al: Risk factors for end stage renal disease in children with a posterior urethral valve. J Urol, suppl., 2008; 180: Drozdz D, Drozdz M, Gretz N et al: Progression to end-stage renal disease in children with a posterior urethral valve. Pediatr Nephrol 1998; 12: Nickavar A, Otoukesh H and Sotoudeh K: Validation of initial serum creatinine as a predictive factor for development of end stage renal disease in a posterior urethral valve. Indian J Pediatr 2008; 75: Sarhan O, El Dahshan K and Sarhan M: Prognostic value of serum creatinine levels in children with a posterior urethral valve treated by primary valve ablation. J Pediatr Urol 2010; 6: Denes ED, Barthold JS and Gonzalez R: Early prognostic value of serum creatinine levels in children with a posterior urethral valve. J Urol 1997; 157: 1441.

5 SERUM CREATININE DECREASE AFTER ENDOSCOPIC VALVE ABLATION IN NEONATES 2501 EDITORIAL COMMENT Regardless of initial and ultimate renal function, these authors observed nadir serum creatinine at around age 6 months in a cohort of 14 male infants in whom a posterior urethral valve was managed by neonatal fulguration. As presented, 75% of this decrease generally occurred by age 2 months. While arguing that, absent the expected decrease in creatinine, clinicians can be guided to perform further interventions (refulguration or cutaneous ureterostomy), it is curious that the 4 repeat fulgurations were done not due to unexpectedly high creatinine but rather based on radiographic indications. We are all are entitled to our inconsistencies. The small number of patients limits broad applicability of these findings. Still, the concept seems useful and, if borne out by further studies, many of us will follow the decrease in creatinine with time in valve cases for whatever benefit. George Steinhardt Wayne State University Helen DeVos Children s Hospital Grand Rapids, Michigan REPLY BY AUTHORS It has been our consistent practice to perform repeat valve ablation guided by the urethral appearance on voiding cystourethrogram. During the course of this study, which was retrospective in nature, we recognized that repeat ablation may not add substantially to the rate of the serum creatinine decrease. In our view this finding adds to the existing debates on the definition of adequate valve ablation, and the role of repeat ablation and high diversion, if any. We hope that this finding along with the other findings in our study will provide a useful platform for future studies aimed at answering these questions.