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ORIGINAL ARTICLE
Year : 2023  |  Volume : 28  |  Issue : 1  |  Page : 29-34
 

Overlooked factors causing renal damage in vesicoureteric reflux!


Pediatric Surgery, Park Medical Research and Welfare Society, Kolkata, West Bengal, India

Date of Submission15-May-2022
Date of Decision07-Oct-2022
Date of Acceptance08-Oct-2022
Date of Web Publication10-Jan-2023

Correspondence Address:
Uday Sankar Chatterjee
356/3 Sahid Khudiram Bose Sarani, Kolkata - 700 030, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaps.jiaps_65_22

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   Abstract 


Introduction: Vesicoureteric reflux (VUR), recurrent urinary tract infection (RUTI), febrile urinary tract infection (FUTI), renal scarring, and renal damage are intimately related. Key factors of renal damage in VUR are suspected to be RUTI and FUTI. Hence, conventional treatments are targeted toward the prevention of RUTI and FUTI. However, literatures have witnessed that control of infection is not sufficient enough. That means we are missing some hidden, enigmatic, or overlooked factors which are essentially responsible for renal damage. We know RUTI occurs from the stasis of urine in system and stasis might occur from obstruction somewhere in system. Moreover, obstruction builds up back pressure in the bladder and ureters, and ultimately in kidneys; that pressure is independently harmful to renal function. Pressure is further harmful if this joins together with infection. We know that RUTI and FUTI along with pressure in the urinary tract are harmful to renal parenchyma. Nevertheless, search for the nexus of obstruction, pressure, stasis, infection, and damage (OPSID) of renal function is not yet focused on in VUR research. In this retrospective study on secondary VUR, we would like to find the overlooked factors or nexus of OPSID associated with VUR causing renal damage.
Patients and Methods: A total of 170 renal units of 135 patients with VUR resulted from the posterior urethral valve and from repaired bladder exstrophy, from March 2005 to April 2019, had adequate data regarding control/correction of obstruction and urodynamic studies. The mean patient's age was 2.8 years (range 1 day–14 years). The diagnosis of VURs was made with postnatal cystogram in patients of the posterior urethral valve and of repaired continent augmented bladder exstrophy. We do cystogram not micturating cystogram following ultrasonography if showing dilated ureter/s. If we find no residual in ureter/s after 30 min in cystogram, we label it as “rise and fall” VUR (raf_VUR), i.e., without obstruction. On the other hand, if there is post void residual in ureter/s for more than 30 min, we label it as “rise and stasis” VUR (ras_VUR) means combination of VUR with uretero vesical junction obstruction (UVJO). Along with this, all patients were followed up with albumin creatinine ratio, creatinine clearance, USG Renometry, DTPA renal scan, uroflowmetry, and urodynamic study (UDS). Repeat cystoscopy, if necessary, was done following UDS for secondary bladder neck incision (BNI) or for repeat BNI if necessary.
Results: Mean duration of follow-up was 7.2 years (range 3–14 years). Out of 170 renal units, 132 renal units had VUR without VUJO, i.e., raf_VUR and 38 renal units had ras_VUR. All patients of UVJO were relieved either with anticholinergics or with DJ stenting or by re-implantations. Twenty-nine patients out of 135 had high pressure on UDS, and they needed BNI. We were able to prevent upstaging of chronic kidney disease (USCKD) in all 135 patients.
Conclusions: Our tangible goal of treatment in VUR is the prevention of USCKD. We differentiated raf_VUR from ras_VUR with cystogram. Patients with ras_VUR and patients with raf_VUR with high bladder pressure were actively treated. This particular subset VUR was treated with prophylactic antibiotic and surgical corrections. We prevented renal damage by eliminating obstruction and stasis which helped to prevent RUTI and FUTI. Possibly, similar management might also help to manage “primary VUR.” Possibly those overlooked factors which are essentially responsible for renal damage are veiled in nexus OPSID of the kidney.


Keywords: Bladder pressure, chronic kidney disease, stasis of urine, urinary tract infection, urodynamic study, vesicoureteric reflux


How to cite this article:
Chatterjee US, Basu AK, Mitra D, Basak D. Overlooked factors causing renal damage in vesicoureteric reflux!. J Indian Assoc Pediatr Surg 2023;28:29-34

How to cite this URL:
Chatterjee US, Basu AK, Mitra D, Basak D. Overlooked factors causing renal damage in vesicoureteric reflux!. J Indian Assoc Pediatr Surg [serial online] 2023 [cited 2023 Feb 8];28:29-34. Available from: https://www.jiaps.com/text.asp?2023/28/1/29/367389





   Introduction Top


It is a common belief among pediatrician, surgeons, and urologists that vesicoureteric reflux (VUR) means recurrent urinary tract infection (RUTI), febrile urinary tract infection (FUTI), renal scaring or renal damage. On the other hand, literatures have mentioned that we are possibly missing some other factors, other than RUTI or FUTI; those are responsible for renal damage. About 30 years back, Rushton et al. mentioned that renal scaring with VUR is 40% and surprisingly scaring is 43% without VUR![1] Recently, Wang et al. have mentioned that Randomised Intervenion for Vesicoureteric Reflux (RIVUR) trial has failed to prevent renal scaring even with the prevention of infection. It remains unclear following RIVUR trial;[2] why new renal scarring developed without RUTI? Why there is ongoing renal damage without RUTI? In between those decades, Snodgrass et al. further added that even the combination of VUR and FUTI may not be able to do renal damage![3] Possibly, there are other missed or overlooked factors other than RUTI and FUTI. Now, we believe that there is an undefined, enigmatic subset of VUR which cause renal damage.

Hence, let us consider VUR as a “structural disease” for better appreciation just like horse-shoe kidney or retrocaval ureter, unless and until causing renal damage. We do not go for “prophylactic surgery” for horse-shoe kidneys or retrocaval ureter unless and until causing problem. All VURs are not causing problem or renal damage. Nevertheless, apprehension was there due to a lack of monitoring investigations; before the arrival of urodynamic study (UDS), DTPA scan, concept of creatinine clearance (CCr), and newer concept of CKD. Newer antibiotics are highly effective in controlling FUTI. So why should we go for “prophylactic surgery” with apprehension or with justification of renal damage! Rather we have to find out the real wrongdoer or that particular subset of VUR which causes renal damage.

It is well-known fact that VUR has got bad liaison with RUTI and FUTI. Pediatric physicians and surgeons are apprehended of RUTI and FUTI that might deteriorate renal functions, i.e., decrease in glomerular filtration rate (GFR) and upstaging of chronic kidney disease (USCKD). However, keeping RUTI and FUTI under control is not showing a lucent explanation as glimpse the silver lining. Understanding those missed factors might find out a subset of VUR that would need active treatment of VUR as well as we might shun overtreatment VUR.

We know RUTI and FUTI occur from the stasis of urine in system, and stasis occurs due to obstruction somewhere in system. Similarly, obstruction builds up back pressure in bladder and in ureters and ultimately in kidneys; that might damage renal functions. We know that RUTI or FUTI along with pressure is further harmful for renal parenchyma [Figure 1]. Nevertheless, the nexus of obstruction, pressure, stasis, infection, and damage (OPSID) of kidney are not yet holistically studied both in primary and secondary or other VURs.
Figure 1: Nexus of OPSID (Obstruction, Pressure, Stasis, Infection, and Damage).

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Actually, all VURs are secondary unless proved as primary[4] with necessary modern investigations invented afterward. That is why, in this retrospective study, we would like to share our experience in the management of secondary VUR as well as to find out that subset of patients with VUR that might need active treatment.


   Patients and Methods Top


A total of 165 patients with VUR from PUV and following reconstruction of exstrophy bladder were treated at our center from March 2005 to April 2019. Out of 165 patients, 135 patients (170 renal units; n = 146 from PUV and n = 24 from exstrophy bladder) had adequate data regarding control/correction of obstruction and urodynamic studies, etc. The mean patient's age was 2.8 years (range 1 day–14 years).

The diagnosis of VUR was made with cystogram following fulguration in PUV patients and at follow-up in patients with repaired continent bladder exstrophy. We did MCB (Mitra, Chatterjee, Basu) cystograms not MCU following USG showing dilated ureter/s as mentioned by some authors.[5] In MCB cystogram, as mentioned, we introduced contrast in the bladder. Absence of VUR following MCB cystogram indicates uretero vesical junction obstruction (UVJO). On the other hand, following the presence of VUR, we released catheter to empty the contrast from bladder and ureters. We labeled VUR as “rise and fall” VUR (raf_VUR) if we had found no residual in ureter/s after 30 min [Flow chart 1]. That was an “innocent VUR” i.e., without obstruction [Figure 2]. In another group, we had found stasis of post-void residual in ureter/s for more than 30–180 or more minutes. We labeled those VUR as “rise and stasis” VUR (ras_VUR); which means combination of VUR with UVJO. Combination VUR with UVJO confirmed post void residual of contrast in ureters persisting [Figure 3] following MCB and their progression or regression was monitored with the diameter of calyx, ureters, and cortical thickness by USG Renometry (USGR) during follow-up as mentioned by some authors.[5] All 19 patients with exstrophy bladder were continent, either with CIC or natural Void or with both. However, had VUR in 24 renal units. Superficial bladder neck incision (BNI) was done in two continent patients with repaired exstrophy.

Figure 2: Showing raf_VUR or rise and fall VUR or VUR without obstruction. Contrast coming down within 30 min. VUR: Vesico-ureteric reflux, raf_VUR: “Rise and fall” VUR

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Figure 3: Showing ras_VUR or rise and stasis VUR or VUR with obstruction. Stasis of contrast more than 2 h. VUR: Vesico ureteric reflux, ras_VUR: “Rise and stasis” VUR

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All patients were followed up with albumin creatinine ratio (ACR), CCr to monitor USCKD, USGR, DTPA renal scan, and uroflowmetry. All patients were advised for UDS, particularly for Pdet, Pdet Qmax, and DLPP to exclude or confirm increased bladder pressure from outlet obstruction. Repeat cystoscopy, if necessary, was done following UDS for secondary BNI or to repeat BNI if necessary. Following BNI in patients with suspected UVJO were kept on anticholinergics for few months and monitored with USGR, ACR and CCr. We did DJ stenting [Figure 4] or re-implantations if the deterioration of renal function was found to be >10% from the previous level even with anticholinergics. During the reimplantation of ureters, caliber of ureters was thicker due to muscular hypertrophy. Hence, those ureters were not tapered, unlike the thinner wall of ureter with raf_VUR and minimal tunnels through thicker bladder wall were created to avoid re-obstruction.
Figure 4: Post evacuation residual in ureter for >3 h (a) After 2 months, cystogram with DJ in situ, (b) Contrast coming down in 10 min (c) Almost whole of contrast came down within 30 min (d)

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   Results Top


The mean duration of follow-up was 7.2 years (range 3–14 years). One hundred and thirty-two units had VUR without VUJO, i.e., raf_VUR, i.e., contrast went up and came down within 15–30 min [Figure 2]. We found ras_VUR in 38 units following MCB i.e., combination of VUR with UVJO [Figure 3]. UVJO was relieved in 26 out of 46 units following anticholinergics for 6 months in USGR, CCr, and ACR. Twelve units responded in 8 weeks with DJ stent [Figure 4]. Another eight units got re-implantations for a combination of VUR with UVJO as obstruction was not relieved with DJ stenting. Twenty-nine out of 135 patients had high pressure and pressure-flow (Pdet, Pdet Qmax) on UDS, and they needed BNI [Flow chart 1]. Superficial BNI was done also in two continent patients of repaired exstrophy. Following BNI they maintained continence and amount of urine through the natural void increased.


   Discussions Top


As per International consensus, any structural (e.g., even minimal caliectasis) or functional (e.g., microalbuminuria) changes for >3 months are labeled as CKD and GFR dictates the stages not the serum level of creatinine. Hence, most patients of VUR are in CKD in different stages. Accordingly, our goal of treatment is not prevention of CKD but prevention of USCKD. In earlier stages of CKD, gradual renal deterioration might not be comprehended only with serum creatinine, as serum creatinine start to cross normal range after stage III of CKD, i.e., following the destruction of ~ 50% of renal parenchyma. That's why; we followed renal function with CCr, not with serum creatinine and not even with e-GFR calculators to monitor stages of CKD. Hence, the prevention of USCKD remained our primary endpoint for management, similar to other authors.[5]

None of the imaging strategies are universally accepted.[6] There is no investigation mentioned in literature to diagnose a combination of VUR with UVJO. Most of the literature mentioned that this type of obstruction is “functional” and wanes off without interventions. However, no study regarding this type of “functional obstruction” is available that would have shown no deterioration of GFR in long term despite ras_VUR. Actually, we were unaware of this phenomenon of raf_VUR and ras_VUR due to nonavailability of this kind of radio-imaging, like MCB, from western literature. However, it is easy to comprehend the mechanics of MCB cystogram. It may be dubbed physics in physiology. Now the query is how UVJO occur following bladder outlet obstruction?

Following bladder outlet obstruction, detrusor exercises its muscle power to overcome obstruction; that results in hypertrophy of detrusor as a whole as well as hypertrophy around UVJ that might cause UVJO.[5],[7] Now the query is, how the obstruction could be relieved by DJ stent?

From endourological procedures, particularly in children, we knew and learned that inserted DJ stent in ureter for few days, increases the caliber of VUJ to allow easy instrumentation. Hence, we repurposed the same procedure here.

Why we have paid importance on raf_VUR and ras_VUR?

We have tried to quantify the duration of stasis or dwell time in VUR through ras_VUR and raf_VUR. Obstruction, stasis, or pooling in system offers dwell time for microbial multiplications. Longer the duration of stasis or pooling means longer dwell time. Hence, the growth of microbes is proportionally more; similarly the infection. Doubling (doubling time of E-coli is ~ 20 min) of microbial growth in geometric progression needs dwell time. If there is free flow or free drainage, dwell time is almost nil or minimal. Hence, the chance of infection is nil or minimal. We can guesstimate the chance of RUTI from ras_VUR and raf_VUR.

Our appealing observation on “self limiting secondary VUR” and “nonobstructed, residual, adynamic ureters:” two patients of PUV showed resolution of VUR in cystogram done afterward. However, there was the persistence of HUN. This kind of cystogram would have brought contentment in concerned physician to label the VUR as “spontaneous resolution” and USG would have labeled those dilated ureters as “nonobstructed, residual dilation, adynamic ureters.” However, this “solace” might be detrimental for the kidney. That is why Jeffrey et al.[8] warned and suggested to exclude obstructions at UVJ before labeling the ureters as nonobstructed, residual dilation, or adynamic ureters. Free drainage from ureter is essential to restrain RUTI and FUTI. We guided our treatment plan, keeping the risk of USCKD in protocol alert rather than merely the presence or absence VUR and RUTI. Customarily, it is believed that every VUR, particularly the VUR of high grade, should be promptly treated to prevent UTI and minimize the risk of renal damage. However, it seems that VUR, particularly VUR of high grade, should promptly be investigated to exclude the nexus OPSID to prevent “aggressive” prophylaxis. That is why, the paradigm shifted toward individualized approach for VUR.[6] Antibiotic prophylaxis or surgical correction should be offered to particular subset who are at risk[9] which they are striving to define. Plausibly, that subset of VUR has got nexus of OPSID to cause USCKD. That is why it is recommended to do UDS in all so-called “primary” VUR to exclude obstruction, stasis, and high-pressure system[10],[11],[12],[13] which might cause renal damage along with RUTI, FUTI. In the same way, it is wiser to consider all VURs as secondary; before we diagnose the bonafide primary VUR[4] through necessary investigations.


   Conclusions Top


Most of all previous studies of VUR were done on so-called primary VUR and they have emphasized only on RUTI and FUTI not on the nexus of OPSID. However, from our experiences of secondary VUR, we prevented renal damage by emphasizing that nexus. We know that the classification of VUR was made before the invention of UDS, DTPA renal scan, and newer concept of CKD. Hence, it seems necessary to reorganize the process of understanding of VUR. We hope further prospective studies would validate our insight and apprehension on the nexus of OPSID to make out the subset of VUR for active and aggressive management. Possibly, the nexus of OPSID is active in that subset which is on search in world of VUR research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Rushton HG, Majd M, Jantausch B, Wiedermann BL, Belman AB. Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99mtechnetium-dimercaptosuccinic acid scintigraphy. J Urol 1992;147:1327-32.  Back to cited text no. 1
    
2.
Wang HH, Kurtz M, Logvinenko T, Nelson C. Why does prevention of recurrent urinary tract infection not result in less renal scarring? A deeper dive into the RIVUR trial. J Urol 2019;202:400-5.  Back to cited text no. 2
    
3.
Snodgrass WT, Shah A, Yang M, Kwon J, Villanueva C, Traylor J, et al. Prevalence and risk factors for renal scars in children with febrile UTI and/or VUR: A cross-sectional observational study of 565 consecutive patients. J Pediatr Urol 2013;9:856-63.  Back to cited text no. 3
    
4.
Khoury AE, Wehbi E. Management strategies for vesicoureteral reflux. In: Partin AW editor. Campbell-Walsh-Wein Urology. 12th ed. Philadelphia: Elsevier; 2021. p. 495-517.  Back to cited text no. 4
    
5.
Chatterjee US, Basu AK, Mitra D. Insight into posterior urethral valve from our experience: Paradigm appended to abate renal failure. J Indian Assoc Pediatr Surg 2020;25:297-305.  Back to cited text no. 5
  [Full text]  
6.
Abdelhalim A, Khoury AE. Critical appraisal of the top-down approach for vesicoureteral reflux. Investig Clin Urol 2017;58:S14-22.  Back to cited text no. 6
    
7.
Aslan AR, Kogan BA. The effect of bladder outlet obstruction on the developing kidney. BJU Int 2003;92 Suppl 1:38-41.  Back to cited text no. 7
    
8.
Jeffrey M, Donohoe JM, Weinstein RP, Combs AJ, Misseri R, Horowitz M, et al. When can persistent hydroureteronephrosis in posterior urethral valve disease be considered residual stretching? J Urol 2004;172:706-11.  Back to cited text no. 8
    
9.
Hidas G, Nam A, Soltani T, Pribish M, Watts B, Khoury AE. Primary vesico-ureteric reflux: The need for individualised risk stratification. Arab J Urol 2013;11:8-12.  Back to cited text no. 9
    
10.
Chandra M, Maddix H, McVicar M. Transient urodynamic dysfunction of infancy: Relationship to urinary tract infections and vesicoureteral reflux. J Urol 1996;155:673-7.  Back to cited text no. 10
    
11.
Chandra M, Maddix H. Urodynamic dysfunction in infants with vesicoureteral reflux. J Pediatr 2000;136:754-9.  Back to cited text no. 11
    
12.
Kajbafzadeh AM, Baradaran N, Sadeghi Z, Tourchi A, Saeedi P, Madani A, et al. Vesicoureteral reflux and primary bladder neck dysfunction in children: Urodynamic evaluation and randomized, double-blind, clinical trial on effect of α-blocker therapy. J Urol 2010;184:2128-33.  Back to cited text no. 12
    
13.
Karami H, Razi A, Mazloomfard MM, Javanmard B. Is there any role for urodynamic study in children with high-grade vesicoureteral reflux? Urology 2012;79:888-91.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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