|Year : 2015 | Volume
| Issue : 2 | Page : 63-67
Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves
Divya Bhadoo1, M Bajpai1, Ali Abid1, Gayan Sukanya1, Sandeep Agarwala1, M Srinivas1, Deepika Deka2, Nutan Agarwal2, Ramesh Agarwal3, Rakesh Kumar4
1 Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
4 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||17-Feb-2015|
Prof. M Bajpai
Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aims: Study on prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. Materials and Methods: Antenatally diagnosed hydronephrosis patients were included. Postnatally, they were divided into two groups, posterior urethral valve (PUV) and non-PUV. The studied parameters were: Gestational age at detection, surgical intervention, ultrasound findings, cord blood and follow up plasma renin activity (PRA) values, vesico-ureteric reflux (VUR), renal scars, and glomerular filtration rate (GFR). Results: A total of 25 patients were included, 10 PUV and 15 non-PUV. All infants with PUV underwent primary valve incision. GFR was less than 60 ml/min/1.73 m 2 body surface area in 4 patients at last follow-up. Keyhole sign, oligoamnios, absent bladder cycling, and cortical cysts were not consistent findings on antenatal ultrasound in PUV. Cord blood PRA was significantly higher (P < 0.0001) in PUV compared to non-PUV patients. Gestational age at detection of hydronephrosis, cortical cysts, bladder wall thickness, and amniotic fluid index were not significantly correlated with GFR while PRA could differentiate between poor and better prognosis cases with PUV. Conclusions: Ultrasound was neither uniformly useful in diagnosing PUV antenatally, nor differentiating it from cases with non-PUV hydronephrosis. In congenital hydronephrosis, cord blood PRA was significantly higher in cases with PUV compared to non-PUV cases and fell significantly after valve ablation. Cord blood PRA could distinguish between poor and better prognosis cases with PUV.
Keywords: Amniotic fluid index, antenatal ultrasonography, congenital hydronephrosis, plasma renin activity, posterior urethral valves
|How to cite this article:|
Bhadoo D, Bajpai M, Abid A, Sukanya G, Agarwala S, Srinivas M, Deka D, Agarwal N, Agarwal R, Kumar R. Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. J Indian Assoc Pediatr Surg 2015;20:63-7
|How to cite this URL:|
Bhadoo D, Bajpai M, Abid A, Sukanya G, Agarwala S, Srinivas M, Deka D, Agarwal N, Agarwal R, Kumar R. Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. J Indian Assoc Pediatr Surg [serial online] 2015 [cited 2020 Apr 7];20:63-7. Available from: http://www.jiaps.com/text.asp?2015/20/2/63/151546
The author was awarded Dr. U C Chakraborty Award for presenting this paper in IAPSCON 2014
| Introduction|| |
Posterior urethral valve (PUV) is the commonest cause of renal impairment in boys during early childhood. Despite a systematic approach in deciding choice of therapy in each case,  renal failure is seen in 25-40% of PUV at varying ages. ,, Antenatal diagnosis of hydronephrosis is possible since 1980s but sensitivity and specificity of ultrasound for antenatal diagnosis of PUV remains low. Specific diagnosis is required as PUV is associated with a poorer prognosis as compared to other causes of hydronephrosis which are diagnosed antenatally, such as pelvi-ureteric junction obstruction (PUJO) and vesico-ureteric reflux (VUR). Antenatal diagnosis helps in parental counseling and considering options for antenatal intervention if the diagnosis could be made with precision & foetuses with PUV and poorer prognosis could be identified antenatally. Renal damage in PUV occurs as a result of activation of renin-angiotensin system pathway, in which renin is an early marker. Therefore, the levels of renin must be raised early in those cases with PUV who progress to renal damage. This study was designed to study the role of cord blood plasma renin activity (PRA) and ultrasonography in antenatal diagnosis and prognostication in PUV.
| Materials and Methods|| |
This was a prospective observational study conducted over a period of 1.5 years between January 2013 to June 2014. All patients of antenatally diagnosed hydronephrosis were included. Patients with parental refusal to consent and disappearance of hydronephrosis on 3 rd trimester ultrasound were excluded. Twenty fetuses with normal ultrasound served as controls. Ethical clearance was obtained and patients were enrolled from Obstetrics and Gynecology Outpatient Department (OPD). All the patients were followed up with serial ultrasounds till delivery and severity of hydronephrosis was assessed using the Society of Fetal Urology (SFU) grading [Table 1]. In patients with bilateral hydronephrosis, the higher grade was taken into account while performing the analysis. Two milliliter of cord blood was collected for PRA estimation at the time of cord clamping in ethylenediaminetetraacetic acid (EDTA). Ultrasonography kidney ureter, bladder (USG KUB) to confirm hydronephrosis and baseline renal function tests (RFT) were done at 48 hours of birth. Diagnosis of PUV was confirmed by micturating cystourethrogram (MCU) done soon after birth. Accordingly, patients were divided into two groups: PUV and those with hydronephrosis due to vesico-ureteric reflux and pelvi-ureteric junction obstruction (non-PUV). Patients diagnosed as PUV were managed according to our current clinical practice and published protocol.  All the patients were kept under close follow-up. PRA was repeated at 1 month post-operatively. All PUV patients were followed up with MCU, glomerular filtration rate (GFR) and Tc-99m dimercaptosuccinic acid (DMSA) scan at 1 and 6 months post-operatively. PUV patients were divided into two groups based on GFR values at 6 months post-operatively - those with a GFR <60 and those with a GFR ≥60 ml/min/1.73 m 2 BSA.
Blood sample collected from peripheral vein was immediately transported to laboratory in an ice pack. Upon arrival in the laboratory, plasma was separated by centrifugation (5000 rpm, 15 minutes). The separated plasma was stored at −20°C until assayed. PRA was measured by radioimmunoassay of generated Angiotensin-I using Diagnostics Biochem Canada Inc (DBC) enzyme-linked immunosorbent assay (ELISA) kit (CAN-RA-4600) and values expressed as ng/ml/hr.
The records of all patients were studied regarding gestational age at detection of hydronephrosis, surgical intervention, antenatal ultrasound findings, cord blood and follow-up PRA values, VUR, and renal cortical scarring on DMSA. Data analysis was done using IBM® statistical package for the social sciences (SPSS®) Statistics 20 (IBM, Armonk, New York, United States). Values were reported as number (%) or mean ± standard deviation (range) as appropriate, unless otherwise reported. Associations between categorical variables were examined by Yates corrected Chi-square test. Statistical comparisons between group means were done by the unpaired Student t-test. A P-value < 0.05 was considered significant.
| Results|| |
A total of 46 patients were recruited. Subsequently, 21 of them were excluded as hydronephrosis disappeared in the third trimester scan. The data of remaining 25 patients (10 PUV and 15 non-PUV) were analyzed. In the non-PUV group, 9 (60%) had PUJO including two with bilateral pathology while 6 patients had non-obstructive hydronephrosis.
The mean gestational age at detection of hydronephrosis was 154.6 ± 15.9 days (range: 132-191 days). The mean age was 150.9 ± 12.8 days (range: 134-167 days) and 157.1 ± 17.6 days (range: 132-191 day) in PUV and non-PUV patients, respectively (P = 0.349). Overall, 19 (76%) patients had bilateral and 6 (24%) had unilateral hydronephrosis on initial ultrasound. All 10 PUV patients had bilateral hydronephrosis. In the non-PUV group, 9 (60%) had bilateral while 6 (40%) had unilateral hydronephrosis. The distribution of grades of hydronephrosis was not significantly different among these two groups (P = 0.669) [Table 2].
|Table 2: Grades of hydronephrosis on initial ultrasound (n = 25, P = 0.669) |
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The keyhole sign was seen in 6/25 patients on initial antenatal ultrasound. It was observed in 1/15 (6.7%) non-PUV patients and 5/10 (50%) PUV patients (P = 0.023). The sensitivity and specificity of keyhole sign for diagnosing PUV were 50% and 93.33%, respectively.
The mean amniotic fluid index (AFI) on initial ultrasound was 12.3 ± 3.4 cm (range: 4.6-19.8 cm). It was 10.1 ± 2.8 cm (range: 4.6-16.2 cm) and 13.8 ± 2.9 cm (range: 9.0-19.8 cm) in PUV and non-PUV group, respectively (P = 0.005) [Table 3]. Oligohydramnios was observed in only one (10%) patient in the PUV group and none in the non-PUV group on initial ultrasound. This was however not statistically significant (P = 0.400).
The mean cord blood PRA value for controls and patients were 3.95 ± 1.57 ng/ml/hr (range: 2.26-8.00 ng/ml/hr) and 10.71 ± 5.57 ng/ml/hr (range: 1.51-20.71 ng/ml/hr), respectively. Mean PRA was 7.08 ± 3.28 ng/ml/hr (range: 1.51-12.58 ng/ml/hr) and 16.15 ± 3.36 ng/ml/hr (range: 11.05-20.71 ng/ml/hr) for non-PUV and PUV group, respectively [Figure 1]. The difference in mean cord blood PRA values between the controls and non-PUV group (P = 0.004), PUV and control groups (P < 0.0001), and PUV and non-PUV groups (P < 0.0001) was significant. PRA in PUV group showed a fall post valve ablation [Figure 2]. Mean PRA was10.47 ± 3.26 ng/ml/hr (range: 6.32-16.08 ng/ml/hr) 1 month post-ablation. There was a significant fall in PRA in all patients of PUV post valve ablation (P < 0.0001).
|Figure 1: Mean cord blood plasma renin activity (PRA) values in various groups, NOH: Non-obstrcutive hydronephrosis, All PRA values are expressed as ng/ml/hr|
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|Figure 2: Mean plasma renin activity (PRA) values in posterior urethral valve (PUV) patients: Pre- (cord blood) and post-valve ablation, All PRA values are expressed as ng/ml/hr|
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Baseline serum creatinine (at 48 hours of birth) was within normal limits in 2/10 (20%) PUV patients while it was raised in 8/10 (80%) patients. The mean baseline creatinine was 1.33 ± 0.96 (range: 0.30-3.20 mg/dl).
Vesicoureteric reflux was seen in 9 (90%) of 10 PUV patients at the time of diagnosis. This remained unchanged after valve ablation. Renal cortical scan (DMSA) done 1 month post ablation showed presence of scars in 6 (60%) out of 10 PUV patients. It was unilateral in 4 (66.6%) and bilateral in 2 (33.3%) patients. At 6 months post ablation, scars were unilateral in 6 (60%), bilateral in 2 (20%), and absent in 2 (20%) patients.
The mean GFR was 37.3 ± 18.21 ml/min/1.73 m 2 (range: 12-70 ml/min/1.73 m 2 ) and 61.0 ± 24.44 ml/min/1.73 m 2 (range: 29-89 ml/min/1.73 m 2 ) at 1 and 6 month post valve ablation. Four patients had GFR < 60 while 6 had GFR ≥ 60 ml/min/1.73m 2 BSA at last follow-up.
Mean cord blood PRA among PUV patients with GFR <60 and those with GFR >60ml/min/1.73m 2 BSA was 19.73 ± 0.81 ng/ml/hr (range: 18.72-20.71 ng/ml/hr) and 13.77 ± 1.73 ng/ml/hr (range: 11.05-15.57 ng/ml/hr), respectively (P < 0.0001) [Table 4].
|Table 4: Correlation between Glomerular Filtration Rate (GFR) and Plasma Renin Activity (PRA) in Posterior Urethral Valve (PUV) patients (n = 10) |
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Gestational age at detection of hydronephrosis, bladder wall thickness, amnitotic fluid index, and presence of cortical cysts did not significantly correlate with renal impairment among PUV patients.
| Discussion|| |
Posterior urethral valve is one of the most serious congenital urinary tract anomalies that can lead to deleterious effect on future bladder and renal function.  Despite improvement in survival as many as 25-60% of these patients may have significant impairment in renal function in long-term follow-up. ,,,,
Prenatal diagnosis still remains a challenge inspite of advances made in recent years. The gold standard for post-natal diagnosis is micturating cystourethrography, while pre-natal diagnosis is dependent on routine screening ultrasonography which has a low specificity and is operator dependent. Despite the ability to identify features of bladder outlet obstruction early in fetal development, there is no consensus on how to incorporate early detection into current screening protocols. In centers where antenatal salvage therapies in the form of amnio-infusion and vesico-amniotic shunts are being used, the correct diagnosis of PUV would improve the efficacy of these procedures with respect to case selection. With our current screening strategy, most antenatal interventions are performed well after irreversible damage has occurred. Mortality and long term morbidity from PUV will likely remain unchanged until it is possible to intervene prior to the onset of irreversible renal damage. New biologic markers will allow for more effective diagnosis and intervention at earlier stages of fetal development.
Bajpai et al., first documented the activation of renin angiotensin system (RAS) using PRA, in patients with posterior urethral valves. They found that mean PRA in patients with renal damage was significantly higher as compared to patients with normal renal function. 
In the present study, cord blood PRA was raised in all patients of PUV, whereas no other parameter showed such consistency. Cord blood PRA was raised in 2/3 rd of the patients with PUJO and none of the patients with non-obstructive hydronephrosis. Also, the levels were significantly higher in cases of PUV than those without PUV (P < 0.0001).
Keyhole sign was seen on initial antenatal ultrasound in higher proportion of PUV patients (50% versus 6.7%) (P = 0.023). The sensitivity of this sign for diagnosis of PUV was 50% and specificity was 93.3%. These values were higher compared to those reported in a series published by Bernardes et al. 
Oligohydramnios did not significantly correlate with diagnosis of PUV (P = 0.40). On the other hand, mean AFI values were significantly lower in patients with PUV when compared to non-PUV patients.
Ultimate renal function in PUV patients depends on a number of factors. Renal function deterioration has been linked to age at presentation, GFR, prenatal diagnosis, renal dysplasia, VUR, renal scarring, nadir creatinine during 1 st year of life, upper tract obstruction, bladder dysfunction, and urinary tract infection (UTI). In the recent decades, the choice of therapy in PUV could be easily discerned by a step-wise approach using the Step-Ladder protocol.  Endoscopic valve ablation has become the mainstay of treatment for PUV.  In the present study, all 10 neonates with PUV underwent primary valve ablation using cold knife.
Age at presentation has been suggested as a predictor of renal function in children with PUV. ,, However, the data on this issue are conflicting. Prenatal diagnosis was initially thought to improve the outcome, but earlier studies failed to show that the long-term outcome in prenatally detected PUV patients is better than symptomatic patients detected postnatally. , Hutton et al., reported that antenatal detection before 24 weeks of gestation predicted a poorer prognosis than later detection, with more than 50% of the earlier diagnosed group dead or in renal failure within 4 years of follow-up.  In the present study, there was no significant difference in gestational age at detection among patients who ultimately developed renal impairment and those who did not.
There is tubulointerstitial damage in congenital uropathies mediated through the renin angiotensin system pathway.  The decline in renal function after valve ablation is accompanied by activation of RAS reflected in a gradual rise in PRA.  In an earlier study, fall in GFR, high grade VUR, scars, and raised serum creatinine were not consistent in detecting renal damage in PUV patients but plasma renin activity was found to be high in all such patients. It has been shown that increase in plasma renin activity (PRA) precedes all the other presently accepted criteria of renal damage. ,, In a recent study of 58 patients with PUV, mean PRA was high in all but four patients and the fall in GFR was preceded by a rise in PRA by a significant interval, implying that RAS is activated much earlier before the fall in GFR becomes evident.  Therapy with angiotensin converting enzyme-inhibitors stabilizes and then improves renal function, thereby, retarding the pace of renal damage.  In the present study mean cord blood PRA values were higher in patients who had GFR <60 compared to those with a GFR ≥60ml/min/1.73m 2 BSA (P < 0.0001). A siginificant fall in PRA levels was observed post valve ablation in all patients. These observations were consistent with findings of earlier published studies. ,,,
This study highlights the diagnostic significance of cord blood PRA in infants with PUV. In this pilot study, we have noted that utrasound parameters are not very useful in the antenatal diagnosis of PUV and measurement of PRA in the fetuses may have the potential to differentiate poor from better prognosis PUV patients.
| Conclusion|| |
On antenatal ultrasound keyhole sign, bladder cycling, oligoamnios, and cortical cysts are not consistent findings in posterior urethral valves. In congenital hydronephrosis cord blood PRA is significantly higher in cases with PUV than those without PUV and falls significantly after valve ablation. Cord blood PRA could distinguish between poor and good prognosis group. Our data is promising enough for future trials for cordocentesis-based PRA studies. PRA has the potential to improve efficacy of antenatal diagnosis of PUV.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]