Home | About Us | Current Issue | Ahead of print | Archives | Search | Instructions | Subscription | Feedback | Editorial Board | e-Alerts | Login 
Journal of Indian Association of Pediatric Surgeons
     Journal of Indian Association of Pediatric Surgeons
Official journal of the Indian Association of Pediatric Surgeons         
 Users Online:130 
  Print this page Email this page   Small font sizeDefault font sizeIncrease font size


 
Table of Contents   
ORIGINAL ARTICLE
Year : 2013  |  Volume : 18  |  Issue : 2  |  Page : 74-78
 

Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme-inhibitors on renal recovery


1 Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
4 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication21-Mar-2013

Correspondence Address:
Minu Bajpai
Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9261.109357

Rights and Permissions

 

   Abstract 

Aim: To study renin angiotensin system (RAS) activity after posterior urethral valve ablation and the role of early induction of angiotensin converting enzyme-inhibitors (ACE-I) on the outcome of renal function. Materials and Methods: Thirty four children underwent valve ablation in which therapy with ACE-I was started 40.5 ± 4.1 (range 32-47 months) formed the study group. Post-ACE-I data were collected after mean duration of 18.2 ± 4.0 (12-28 months). Plasma renin activity (PRA), urinary micro albumin, glomerular filtration rate (GFR), and serum creatinine, before and after therapy were monitored. Results: Therapy with ACE-I resulted in a fall in micro albuminuria by 45.7% and 42.0% in patients without and with vesico ureteral reflux, respectively, and improvement in split renal function by 6.6% and 5.9% GFR respectively. A similar response was noted in patients without and with renal scars. Conclusion: The decline in renal function after valve ablation is accompanied by activation of RAS reflected in a gradual rise in PRA. Therapy with ACE-I stabilizes and then improves renal function, thereby, retarding the pace of renal damage.


Keywords: Angiotensin converting enzyme-inhibitors, glomerular filtration rate, microalbuminuria, plasma renin activity, posterior urethral valves, renal scars


How to cite this article:
Bajpai M, Chaturvedi PK, Bal CS, Sharma MC, Kalaivani M. Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme-inhibitors on renal recovery . J Indian Assoc Pediatr Surg 2013;18:74-8

How to cite this URL:
Bajpai M, Chaturvedi PK, Bal CS, Sharma MC, Kalaivani M. Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme-inhibitors on renal recovery . J Indian Assoc Pediatr Surg [serial online] 2013 [cited 2019 Nov 17];18:74-8. Available from: http://www.jiaps.com/text.asp?2013/18/2/74/109357



   Introduction Top


Chronic renal failure (CRF) occurs in a significant number of children with posterior urethral valves (PUVs) and accounts for 16.8% of the population of children with end stage renal disease (ESRD). [1],[2] Renin angiotensin system (RAS) activation as a mediator of renal injury and interstitial fibrosis has been reported in other renal diseases. [3] In a previous communication, [4],[5] we reported that plasma renin activity (PRA) may be helpful in identifying patients with risk of renal damage. In this prospective study, we evaluated the role of RAS blockade by angiotensin converting enzyme-inhibitor (ACE-I) after valve ablation and correlated it with tests of renal function, micro albuminuria, and PRA.


   Materials and Methods Top


Children who underwent valve ablation between the ages of 3 and 7.5 months and managed according to the "step ladder" protocol described previously, [6] formed the study group. Serum creatinine and PRA were measured before, between 1 month and 3 months after valve ablation and then at 1 yearly intervals. All patients had undergone urodynamic studies and adequately treated for any abnormality. During follow-up after valve ablation, we measured urinary micro albumin, renal scars, split renal function (SRF), glomerular filtration rate (GFR), serum creatinine, blood pressure, and episodes of breakthrough urinary tract infection (UTI). GFR was calculated each time using venous blood samples obtained at 60, 90, 150, and 180 min after 99m technetium diethylene triamine penta-acetic acid (DTPA) injection. Renal scars were evaluated by dimercapto succinic acid (DMSA) scan. The records of these patients were reviewed regarding the time of valve ablation and adequacy of ablation on micturating cystourethrogram. The patients with GFR below 50 mL/min/1.73 m 2 , severely scarred kidneys and refluxing units were excluded from the study.

We stratified the patients by the presence/absence of vesico ureteral reflux (VUR) and renal scaring.

Group 1: Patients with no evidence of (e/o) VUR and scar formation (n0 = 13)

Group 2: Patients with e/o VUR but no e/o scar formation (n = 6)

Group 3: Patients with e/o renal scarring but no e/o VUR ( n = 3)

Group 4: Patients with e/o both VUR and scar formation ( n = 12)

State of RAS activation was recorded by measuring PRA by using a commercially available kit. Micro albuminuria was measured by an enzyme immunoassay (normal range 2-20 mg/L). The urinary micro albumin levels were documented before and after RAS blockade using ACE inhibitor (Enalapril) in a dose of 0.14 mg/kg/day. Serum potassium levels were periodically monitored and the data on SRF were taken from the poorly functioning unit.

The pre-valve ablation data were available only for serum creatinine and PRA. In the post-valve ablation phase, (early and late) besides these two tests, data were also available on VUR, DMSA scan, GFR, urinary micro albuminuria, and blood pressure. The first set of these data were available at a mean post-valve ablation period of 1.3 ± 0.6 months (range 1-4 months). Post-ablation period before initiating the therapy with ACE-I subsequent to this point was 40.5 ± 4.1 (range 32-47 months). This period was further divided into, early post-ablation period 9.1 ± 2.2 (range 6-12 months) and late post-ablation period (31.5 ± 4.7 (ranges 24-40 months). The post ACE-I therapy data were collected after mean duration 18.2 ± 4.0; range 12-28 months, this duration reflects the time while the children were receiving ACE-I therapy.

Statistical analysis was carried out using statistical package for the social sciences (SPSS) (SPSS 11.5 Inc. Chicago, Illinois, USA) and the data were presented as mean (SD). Renal function parameters such as GFR, PRA, serum creatinine, and urinary micro albuminuria between different groups of patients has been compared using paired sample t-test. The P values less than 0.05 were considered statistically significant.


   Results Top


The total patients in the study group were 34 and their mean age at the time of valve ablation was 3.5 ± 1.9 (range 3-7.5 months). The duration of follow-up before initiating therapy with ACE-I was 40.5 ± 4.1 (range 32-47 months). Mean follow-up after initiating therapy with ACE-I was 18.2 ± 4.0 (range 12-28 months).

Early period after valve ablation (1.3 ± 0.6 months; range 1-4 months): Before and after valve ablation fall in PRA and serum creatinine was sustained [Table 1]. During this period a 66.9% fall in PRA and 23.1% fall in serum creatinine have been noted in group 1. Sixty seven % fall in PRA and 33.3% fall in serum creatinine have been noted in group 2. In group 3 it was 71.4% fall in PRA and 25.0% fall in serum creatinine and in group 4, the fall in PRA was 70.7% and in serum creatinine it was 40.0% from the pre-valve ablation value.
Table 1: Plasma renin activity and serum creatinine levels before and after valve ablation


Click here to view


Late period after valve-ablation but before starting ACE-I therapy (31.5 ± 4.7 months; range 24-40 months) [Table 2]: During this phase gradual deterioration in GFR, marginal rise in PRA and serum creatinine was noted in all the groups. GFR fell in18.5%, PRA raised in 4.0% and 30.0% rise in serum creatinine has been noted in group 1. In group 2, it was 24.2% fall in GFR and 13.3% rise in PRA followed by the rise in serum creatinine by 75.0%. In group 3, fall in GFR was 13.0%, rise in PRA was 10.0% and rise in serum creatinine was 33.3%. In group 4, the fall in GFR was 70.7% followed by the rise in PRA by 23.5% and rise in serum creatinine by 8.3% has been noted.
Table 2: Status of glomerular filtration rate, plasma renin activity and serum creatinine levels early and later phase after valve-ablation


Click here to view


Period after initiating therapy with ACE-I (mean duration 18.2 ± 4.0; range 12-28 months): During this phase, we additionally assessed urinary micro albuminuria before and after initiating therapy with ACE-I. A marginal rise of 5.9% in GFR, rise in PRA by 19.2%, fall in serum creatinine by 23.1% and significant fall in urinary micro albuminuria by 55.0% has been noted in group 1. In group 2 the corresponding figures were 5.8% rise in GFR, 21.6% rise in PRA, 28.6% fall in serum creatinine, and 55.6% fall in urinary micro albuminuria. In group 3 a rise in GFR was 4.2%, rise in PRA by 48.4%, fall in serum creatinine by 5.5% and fall in urinary micro albuminuria by 64.6% were noted. In group 4 the observations were 5.7% rise in GFR, 17.7% rise in PRA, 23.8% fall in serum creatinine and 55.3% fall in urinary micro albuminuria. Observations on blood pressure were inconclusive in all the groups. The marginal rise in PRA seen after ACE-I therapy is known to occur after ACE-I therapy and is due to the negative feedback from reduction in angiotensin II production.


   Discussion Top


The progression to CRF even after successful ablation of PU valves is multi-factorial. Although, the mechanisms involved in the progression of renal failure are still unclear, alterations in RAS may have a crucial role by influencing glomerular hemodynamics. [6],[7],[8] PRA is a primary player in the RAS pathway and Angiotensin II is the final mediator of tubulo interstitial damage. [9],[10] During the early stages of renal damage, tubular functional abnormalities are more pronounced than the decline in GFR. [11],[12] After valve-ablation, the current practice is to follow-up these patients by conducting periodic routine tests of renal function, such as estimation of GFR, serum creatinine and performing DMSA scan and treating infection as and when it occurs. A substantial proportion of patients still progress to end-stage renal disease before renal function begins to stabilize. [6],[13]

The presence of VUR and renal scars are associated with poor prognosis in patients with PUV. Although, there is a high-rate of spontaneous resolution of reflux following decompression of the lower urinary tract, yet, it may take several years. [14],[15],[16] Analysis of results of therapy with ACE-I revealed that [Table 3] response to ACE-inhibitors in reducing micro albuminuria was significant even in the absence of VUR (55.0%) viz-a-viz with VUR (55.6%). In both the groups ACE-inhibitors helped in not only reducing micro albuminuria but also led to improvement in GFR [Table 3] and serum creatinine. It may be inferred from these data, that, there is ongoing renal damage even in the absence of VUR and ACE-inhibitors have a role in retarding the pace of renal damage even in this group. Similarly, ACE-inhibitors help in stabilizing renal function while waiting for spontaneous resolution of VUR, when it exists.
Table 3: Glomerular filtration rate, Plasma renin activity, serum creatinine and urinary micro albumin levels before and after initiating therapy with angiotensin converting enzyme-inhibitors


Click here to view


The rise in PRA between early and late phase after valve-ablation reflects that RAS down regulation achieved immediately after valve-ablation and sustained for a period of time, thereafter is not sustained in the long-term. Gradual re-activation of RAS becomes apparent in the form of rising PRA and is accompanied by deterioration in renal function parameters. This should be distinguished from the rise in PRA observed after ACE-I therapy [Table 3], which is accompanied by improvement in renal function parameters. In the latter situation, the rise in PRA is similar to the observed effect of ACE-I in anti-hypertensive therapy, wherein, a reactive rise in PRA has been reported. [17]

A large number of patients with PUVs have renal dysplasia, which is detected on DMSA scan as photopenic areas similar to the new renal scars. There is unanimous agreement [18],[19] on the importance of hypertension and proteinuria as prognostic factors in long-term renal outcome. Paradoxically, monitoring for hypertension and proteinuria begins when there is a significant fall in creatinine clearance. [20] Although, higher mean PRA has been reported in patients with long standing renal damage, yet, prior to our report, [8] information on PRA was not available in patients without renal scars. In the present study, we found that high PRA was associated with a steady decline in renal function and elevated levels of micro albuminuria even in patients who did not have renal scars [Table 3].

It may be noted that in response to ACE-I there was a reduction in micro albuminuria even when scars were not present viz-a-viz when scars were present by 54.0% and 64.2%, respectively [Table 3]. ACE-I also helped in stabilizing and improving GFR and serum creatinine [Table 3].

A notable feature in this study was the high PRA and micro albuminuria even when scars were not seen on DMSA scan. It is possible, that, early periglomerular fibrosis represents 'nascent scars.' This may be the forerunner of scars visible later on as photopenic areas on DMSA scan, as the disease advances. The beneficial effects of ACE-I, esp. in chronic kidney diseases are well established [21],[22],[23],[24] and it has been confirmed that ACE-I are more effective than other anti-hypertensive agents in slowing the progression to end-stage disease in non-diabetic patients. [22] Although, none of our patients were hypertensive, yet, we still found a significant reduction in micro albuminuria.

In the present study, we have observed improvement in GFR even in patients without renal scarring, thus, underscoring the need for initiating ACE-I therapy early, thereby, retarding the pace of renal damage and preventing future scarring. A substantial number of these patients progress to renal failure because of the current lag time between initiating treatment for RAS blockade and remission. Our data suggest that any improvement in long-term survival of these patients will depend on preservation of renal function by detecting early RAS activation and retarding the consequences of hyperfiltration. Our study also highlights the urgent need for a randomized controlled trial for establishing PRA as an early prognostic marker as well as exploring the need for pre-emptive therapy with disease modifying agents.

 
   References Top

1.Parkhouse HF, Barratt TM, Dillon MJ, Duffy PG, Fay J, Ransley PG, et al. Long-term outcome of boys with posterior urethral valves. Br J Urol 1988;62:59-62.  Back to cited text no. 1
    
2.Kohaut EC, Tejani A. The 1994 annual report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1996;10:422-34.  Back to cited text no. 2
    
3.Yarger WE, Schocken DD, Harris RH. Obstructive nephropathy in the rat: Possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in postobstructive renal function. J Clin Invest 1980;65:400-12.  Back to cited text no. 3
    
4.Bajpai M, Pratap A, Tripathi M, Bal CS. Posterior urethral valves: Preliminary observations on the significance of plasma Renin activity as a prognostic marker. J Urol 2005;173:592-4.  Back to cited text no. 4
    
5.Bajpai M, Dave S, Gupta DK. Factors affecting outcome in the management of posterior urethral valves. Pediatr Surg Int 2001;17:11-5.  Back to cited text no. 5
    
6.Bajpai M, Dave S. Prognostic factors in posterior urethral valves and the stepladder protocol. In: Bajpai M, Gearhart JP, Hjalmas K, editors. Progress in Pediatric Urology. Vol. 4. New Delhi: Penwel Publishers; 2001. p. 39-51. Available from: http://www.paediatric-urologyonline.com.  Back to cited text no. 6
    
7.Roth KS, Carter WH Jr, Chan JC. Obstructive nephropathy in children: Long-term progression after relief of posterior urethral valve. Pediatrics 2001;107:1004-10.  Back to cited text no. 7
    
8.Bajpai M, Pal K, Bal CS, Gupta AK, Pandey RM. Role of plasma renin activity in the management of primary vesicoureteric reflux: A preliminary report. Kidney Int 2003;64:1643-7.  Back to cited text no. 8
    
9.Campbell SE, Janicki JS, Weber KT. Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. J Mol Cell Cardiol 1995;27:1545-60.  Back to cited text no. 9
    
10.Wolf G, Killen PD, Neilson EG. Intracellular signaling of transcription and secretion of type IV collagen after angiotensin I induced cellular hypertrophy in cultured murine proximal tubular cells. Cell Regul 1991;2:219.  Back to cited text no. 10
    
11.Hostetter TH. Mechanisms and functional manifestations of tubulointerstitial nephritis. In: Jacobson H, Striker GE, Klahr S, editors. The Principles and Practice of Nephrology. 2 nd ed. St. Louis: Mosby; 1995. p. 202-7.  Back to cited text no. 11
    
12.Marcussen N. Atubular glomeruli and the structural basis for chronic renal failure. Lab Invest 1992;66:265-84.  Back to cited text no. 12
    
13.Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: Renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med 2002;136:604-15.  Back to cited text no. 13
    
14.Glassberg KI. Upper tract outcome in posterior urethral valve patients. In: Bajpai M, Gearhart JP, Hjalmas K, editors. Progress in Pediatric Urology. Vol. 4. New Delhi: Penwel Publishers; 2001. p. 94-109. Available from: http://www.paediatric-urologyonline.com.  Back to cited text no. 14
    
15.Johnston JH. Reflux secondary to severe urethral obstruction. In: Management of Vesicoureteric Reflux. Baltimore: The Williams and Wilkins Co.; 1984.  Back to cited text no. 15
    
16.Lal R, Bhatnagar V, Mitra DK. Upper-tract changes after treatment of posterior urethral valves. Pediatr Surg Int 1998;13:396-9.  Back to cited text no. 16
    
17.Campbell RC, Ruggenenti P, Remuzzi G. Halting the progression of chronic nephropathy. J Am Soc Nephrol 2002;13:S190-5.  Back to cited text no. 17
    
18.Woolf AS, Thiruchelvam N. Congenital obstructive uropathy: Its origin and contribution to end-stage renal disease in children. Adv Ren Replace Ther 2001;8:157-63.  Back to cited text no. 18
    
19.Churchill BM, Antoine EK, Merguerian PA, Houle AM. Pediatric urinary tract obstruction. Urol Clin North Am 1990;17:343-60.  Back to cited text no. 19
    
20.Sheldon CA, Geary DF, Shely EA, McLorie GA. Surgical considerations in childhood end-stage renal disease. Pediatr Clin North Am 1987;34:1187-207.  Back to cited text no. 20
    
21.Konda R, Orikasa S, Sakai K, Ota S, Kimura N. The distribution of renin containing cells in scarred kidneys. J Urol 1996;156:1450-4.  Back to cited text no. 21
    
22.Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: A meta-analysis of randomized trials Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997;127:337-45.  Back to cited text no. 22
    
23.GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857-63.  Back to cited text no. 23
    
24.Izzo JL Jr, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich) 2011;13:667-75.  Back to cited text no. 24
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
Print this article  Email this article

    

 
  Search
 
  
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (355 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
    Materials and Me...
   Results
   Discussion
    References
    Article Tables

 Article Access Statistics
    Viewed1912    
    Printed97    
    Emailed0    
    PDF Downloaded150    
    Comments [Add]    

Recommend this journal


Contact us | Sitemap | Advertise | What's New | Copyright and Disclaimer 

  2005 - Journal of Indian Association of Pediatric Surgeons | Published by Wolters Kluwer - Medknow 

Online since 1st May '05