# Vesicoureteral Reflux, Reflux Nephropathy,  and End-Stage Renal Disease

Authors: Paul Brakeman
Journal: Advances in Urology
 (2008)

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## Abstract

Objective. To review the contribution of vesicoureteral reflux and reflux nephropathy to end-stage renal disease.
Data Source. Published research articles and publicly available registries.
Results. Vesicoureteral reflux (VUR) is commonly identified in pediatric patients and can be associated with reflux nephropathy (RN), chronic kidney disease (CKD), and rarely end-stage renal disease (ESRD). Patients with reduced GFR, bilateral disease, grade V VUR, proteinuria, and hypertension are more likely to progress to CKD and ESRD. Because progression to ESRD is rare in VUR and often requires many decades to develop, there are limited prospective, randomized, controlled trials available to direct therapy to prevent progression to ESRD.
Conclusions. Identification of patients with increased risk of progression to CKD and ESRD should be the goal of clinical, biochemical, and radiological evaluation of patients with VUR. Treatment of patients with VUR should be directed at preventing new renal injury and preserving renal function.


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## Body

## 1. Introduction

Vesicoureteral
reflux (VUR) is a common finding in pediatric patients. Approximately 1/3 of
patients who have had a urinary tract infection (UTI) have VUR and 9–20% of patients
with prenatal hydronephrosis have VUR when tested postnatally [1]. The prevalence of VUR in the
general pediatric population has been estimated recently to be as high as 17.2%
[1, 2].
Some patients with VUR develop reflux nephropathy (RN), some patients with RN
develop chronic kidney disease (CKD), and a small number of patients progress
to end-stage renal disease (ESRD). While UTI and VUR are relatively common,
ESRD is rare in the pediatric population with an unadjusted incident rate of
14.8 per million patients per year in 2005 for ages 0–18 years [3]. The goal of this article is
to describe the contribution of VUR to ESRD in pediatric patients, define risks
for progression, and review data indicating what treatments may prevent
progression to ESRD for patients with VUR.


## 2. Renal Pathophysiology in Reflux Nephropathy

The mechanisms for
the development of ESRD in VUR are complex. In animals, when the flow of urine
is obstructed in the developing kidney a series of abnormalities occur
including (1) arrest of glomerular maturation, (2) glomerulosclerosis, (3)
ischemia and necrosis of some tubular cells, (4) apoptosis of other tubular and
collecting duct cells, (5) interstitial inflammation, proliferation, and fibrosis,
and (6) tubular dilatation and atrophy [4–6].
In addition, in animals and humans there is evidence that scarring occurs in
compound papillae where intrarenal reflux is present [7]. In humans, RN is usually identified
as renal scarring as defined on dimercaptosuccinic acid
(DMSA) scan in a patient known to have VUR. It is important to note that
the causality is not completely clear as some patients have renal scarring by
DMSA scan but do not have VUR. It is also clear that pyelonephritis in the
presence of VUR may lead to new scarring on DMSA scans; however, some patients
with VUR have RN with renal scarring by DMSA scan at the time of diagnosis
whether or not they have had a urinary tract infection. This is highlighted by
the fact that some patients diagnosed at birth have renal scarring as defined
by DMSA scan [8, 9].
One possible explanation for this is that damage to the kidney may occur
embryonically due to VUR. Alternatively, some of the genes that control normal
development of the ureters and ureterovesicular junction also control renal
development. Thus VUR may  be associated with either macroscopically abnormal
renal development or subtle developmental changes that predispose the kidney to
developing scarring as identified by DMSA scan. A portion of the patients who
develop ESRD related to RN may have abnormally developed kidneys that
progressively worsen over time with further decrease in renal function
exacerbated by proteinuria, hypertension, and episodes of pyelonephritis. This
is highlighted by the fact that in multiple studies, correction of VUR does not
completely prevent the formation of new scars [10, 11],
indicating that there may be worsening renal pathology even once VUR has been
corrected in some patients.


## 3. Reflux Nephropathy Is a Major Cause of ESRD in Children

Multiple registries in the United States  and internationally
have identified RN as an important cause of ESRD. For adults, RN is not a very
common cause of ESRD in children. In the USRDS database, RN is not specifically listed as
an etiology for ESRD; however, obstructive uropathy not due to ureteropelvic
junction or ureterovesicular junction obstruction is one of the less common
causes for ESRD. For all ages, obstructive uropathy accounted for 0.6% of the point
prevalent cases for 2005 [3]; whereas diabetes accounted
for 36%. The incidence of obstructive uropathy in the USRDS has been stable at
approximately 0.3% since 1994 [12], but has increased from 0.1%
for all ages for 1989–93 [13] to 0.3% for the time periods 1994–98 [12], and 1999–2003 [3]. In the north American pediatric
population, RN is reported as the 4th leading cause for dialysis and
transplantation with 5.3% of transplant patients having a diagnosis of RN and
3.5% of dialysis patients having a diagnosis of RN [14]. The incidence of RN in the
pediatric population has remained stable from 2003 to 2007 [14, 15]. It is important to note that
the 2nd and 3rd leading causes for dialysis and transplantation in children are
obstructive uropathy and aplasia/hypoplasia/dysplasia either of which can be
intertwined with RN [14]. Furthermore, in this
pediatric population another 2.6% of the transplant patients and 2% of dialysis
patients carry a diagnosis of prune belly syndrome which is a disease of
urinary obstruction in uteroand is often associated with VUR [14]. The accuracy of these
registries is dependent on those entering data and diagnostic codes and thus
may overrepresent or underrepresent the importance of RN in ESRD. However, in
various international reports reflux nephropathy either alone or in combination
with congenital obstructive disease also is identified consistently as a
leading cause of ESRD [16–21].


## 4. VUR Is Common in Children; However, ESRD Related to VUR Is Rare

In the North
American Pediatric Renal Trials and Collaborative Studies registry, RN accounts
for approximately 5% of the pediatric ESRD population [14]. It is possible to dispute
the accuracy of this figure as this registry depends on voluntary reporting of
data and there is no verification of the accuracy of the assigned diagnoses.
However, if one uses this figure as an estimate and combines it with the annual
incidence of ESRD for ages 0–18 reported by the
USRDS of 14.8 per million, then the incidence of ESRD related to RN in the
pediatric population would be approximately 0.7 per million patients [3, 14]. If one compares this annual
incidence to the estimated prevalence of VUR in the general population, which
has been recently reported as 17.2% or 172 000 per million, it is clear that the vast majority
of patients with VUR do not develop ESRD. Even if one uses older estimates of
the prevalence of VUR in the general population of 1-2% or 10 000 to 20 000 per million patients [2, 22],
VUR is much more common than ESRD.  Since
the most common type of VUR is low-grade VUR or grades I–III VUR, this
implies that lower grade reflux very rarely is associated with decreased renal
function. Given that most patients with VUR do not develop ESRD or even CKD,
much work has centered on identifying those patients with VUR who are at risk
of developing CKD and ESRD. This work has been complicated by the fact that
many older reports on outcomes of VUR were based on datasets from referral
centers, not the general pediatric population, and thus are likely to have a
strong bias towards patients with more severe disease.


## 5. Risk Factors for Progression to CKD and ESRD in Pediatric Patients with VUR

Multiple
retrospective trials have identified factors predictive of progression to CKD and
ESRD in pediatric patients with VUR (Table1). There have been few papers that
have focused solely on progression to ESRD as a primary endpoint in patients
with RN, since, as described above, ESRD in general is a rare event for
patients with VUR. Table 1 lists studies describing risk factors for CKD and
ESRD in patients with VUR. Ardissino et al. retrospectively evaluated the risk of
progressing from CKD to ESRD in a cohort of 322 pediatric patients with VUR and
creatinine clearance (CrCl) <1.25 mL/s per 1.73 m2 body surface
area and found an overall risk of 56% for progressing to ESRD by the age of 20 [21]. Not surprisingly, those
patients with CrCl <0.67 mL/s per 1.73 m2 had a 4-fold increased
risk of progressing to ESRD compared to those with CrCl ≥ to 0.67 mL/s per 1.73 m2. In addition, age at diagnosis was not associated with an
increased risk of progression to ESRD with those diagnosed at age greater than
6 months having no significant difference in risk of progression to ESRD
compared to those diagnosed at age ≤6 months. In this cohort, grade IV reflux
was the most common grade of VUR; however, information on the grade of VUR was
reported for only 51% of the patients, making it difficult to relate risk of
progression to grade of reflux. 29.1% of the patients were either hypertensive or being
treated with antihypertensive medication, demonstrating the association between
hypertension and RN. In addition, 104 of the 322 patients were evaluated for
proteinuria, and approximately 1/3 (34/104) had moderate to severe proteinuria
(uPr/uCr 0.95–7.2). Those patients with moderate to severe proteinuria showed a
statistically significant larger mean rate of CrCl decrease when compared to
those with mild or no proteinuria, thus demonstrating that proteinuria is
associated with ongoing renal deterioration and may be a target for therapies
to prevent progression to ESRD.Table 1
Characteristics of studies reporting CKD and ESRD data for VUR.
StudyN (males)Mean length of F/U in years (range)% with reflux >/= grade 3Incidence of CKD (upper limit of GFR for CKD in mL/s per 1.73 m2)Incidence of ESRDPredictors of ESRD/CKDArdissino, J Urol, 2004 [21]322 (245)>595%N/A—CKD was an inclusion requirement56%Proteinuria, CrCl <0.67 mL/s/1.73 m2Caione, BJU Int, 2004 [23]50 (42)6.3 (1–16)100%54% (1.3)0%Creatinine r >53 umol/L in the first yearNeild, BMC Neph, 2004 [24]44 (22)NRNot reported (NR)N/A—CKD was an inclusion requirementN/AProteinuria, GFR < CrCl <0.83 mL/s/1.73 m2Lahdes-Vasama, NDT, 2006 [25]267 (58)37 (27–48)NR67% (1.5)9%Bilateral scarringMor, BJU Int, 2003 [26]100 (21)20–30NR1% (1.5)0NRSilva, Ped Neph, 2006 [27]735 (208)6.3 (0.5–34)60% of renal units3.1% (<1.25)1.5%HypertensionSilva, Ped Neph, 2006 [28]184 (69)6.5 (1.1–34)100%15%5.4%Bilateral VUR, grade V VUR, diagnosis before 1990, diagnosis at age >24 monthsBecause having CKD
increases the risk of progressing to ESRD in patients with VUR, risk factors
for progressing to CKD are highly likely to be significant predictors for the
progression to ESRD. Several studies have focused on risk factors for
developing CKD in patients with VUR. Silva published data on a retrospective
cohort of 735 pediatric patients with VUR of all grades with 29% of the
patients having high-grade VUR (grades IV and V) [27]. Thus, this cohort exhibited
some selection bias as the rate of high-grade VUR was significantly higher than
reported in studies in the general population. In this cohort, 3% developed CKD
(as defined by GFR <1.25 mL/s per 1.73 m2 body surface area as
estimated by the Schwarz formula) and 1.5% developed ESRD (GFR <0.25 mL/s
per 1.73 m2). Progression to CKD was strongly associated with
hypertension. As part of the same work, Silva et al. evaluated 184 pediatric
patients with severe bilateral reflux (grades III–V) followed at a
single tertiary care center [28]. Mean follow-up was 78.6
months. All patients received daily antibiotic prophylaxis and 15% (27/184) had
surgical reimplantation. In this higher-risk cohort, the estimated probability
of developing CKD was approximately 15% at 10 years postdiagnosis of VUR. In
multivariate analysis, age at diagnosis >24 months, VUR grade V, and
bilateral renal damage were associated with an increased risk for CKD.
Interestingly, diagnosis of VUR after 1990 was associated with reduced risk for
CKD. This data implies that our current diagnosis and treatment of VUR may
reduce the risk of developing CKD. In addition, the estimated risk of CKD was
0% for patients with grade III reflux or a negative DMSA at the time of
diagnosis. The lack of progression to CKD in those patients with a normal DMSA at
diagnosis implies that, perhaps, it is only those kidneys with congenital
lesions or that already have been significantly damaged at diagnosis that are
at risk for development of significant renal impairment.Several
other studies also have focused on high-risk populations of VUR patients. Neild
et al. evaluated a high-risk population of 44 patients with bilaterally scarred
kidneys due to primary reflux or bladder dysfunction and GFR0.25–1.0 mL/s per
1.73 m2 based on either an eGFR using the Jelliffe formulae or
plasma clearance of EDTA [24]. They identified a watershed GFR
of 0.83 mL/s per 1.73 m2 below which the likelihood of progressing
to ESRD increased substantially. In addition, they identified proteinuria as
predictive of increased risk of CKD and were able to demonstrate a protective
effect of ACE inhibitors on the rate of decline of renal function for patients with
eGFR >0.75–0.83 mL/s per 1.73 m2. Caione et al. retrospectively
reviewed 50 patients from Italy with bilateral VUR grades III-V diagnosed in
the first year of life with an average follow-up of 6.3 years [23]. In their cohort, 54% of the
patients developed CKD as defined by eGFR <1.3 mL/s per 1.73 m2.
All were boys, and in multivariate analysis neither number of UTIs nor prenatal
diagnosis modified the likelihood of CKD. In multivariate analysis, a serum
creatinine >53 umol/L significantly increased the likelihood of developing
CKD. These two studies, while both small, appear to demonstrate that there is a
threshold after which renal function declines with much greater frequency to
CKD. In addition, Caione’s study did not identify an association of CKD with
febrile UTIs, implying once again that, perhaps,  patients with severe VUR progress
to CKD due to ongoing inflammation and pathologic changes or developmental
abnormalities rather than acquired damage.


## 6. Very Long-Term Follow-up of VUR Patients

There have been
several other retrospective cohort studies from a variety of populations with very
long follow-up that evaluated the long-term outcome of VUR. For these patients
with very long follow-up, treatment was initiated in some as long as 40 years
ago, and it is possible that current treatment protocols, including more
aggressive treatment of voiding dysfunction, may yield different outcomes than
treatment practices from 40 years ago. In addition, these cohorts from several
decades ago also appear to share a selection bias towards patients with more
severe VUR and higher rates of scarring, perhaps because only the most severe
VUR with recurrent infections was diagnosed in the past. Also, renal scarring
was identified by intravenous pyelogram which is not as sensitive as DMSA
scans; thus, patients identified as having renal scarring had more severe renal
damage. Lahdes-Vasama et al. evaluated a cohort of Finnish patients followed
for an average of 37 years [25]. They attempted to enroll 267
patients with VUR diagnosed between 1955 and 1965 but only were able to report
information on current renal function for 127 of the patients. In this cohort,
12/265 had died due to kidney-related conditions, 7/265 had undergone renal
transplantation, and 1/265 was on hemodialysis. For those who agreed to enroll,
85/127 had GFR <1.5 mL/s per 1.73 m2, 4/127 had GFR
<60 mL/min/1.73 m2,
and 1/127 had GFR <0.50 mL/s per 1.73 m2 based on the
Cockcroft-Gault formula. Among the enrolled patients, 35% had unilateral
scarring and 24% had bilateral scarring by ultrasound, and the patients with
bilateral scarring were significantly more likely to have reduced GFR.
Interestingly, this Finnish cohort had no increased prevalence of hypertension
compared to the rest of the Finnish population. The study implies that
approximately 7% of patients with VUR progress to ESRD; however, the study was
limited because they were unable to evaluate grades of reflux or the presence
or treatment of voiding dysfunction, and there was a very high rate of renal
scarring that was severe enough to be measurable by ultrasound. These factors
indicate that there may have been significant selection bias in this cohort.El-Khatib et al.
reported data from 293 patients who were diagnosed with RN or VUR between 1971
and 1986 in Australia [29]. In this group, most patients
were females who presented with febrile UTI; there was no information on VUR
grade; and 89% of the patients had renal scarring on IVP. Thus, this population
was highly selected for patients with more severe RN than a general population
of patients with VUR. In this cohort, 37% demonstrated deterioration in renal
function based on rising serum creatinine. In multiple regression analysis, the
independent risk factors for rise in serum creatinine were proteinuria,
hypertension, elevated creatinine at presentation, bilateral VUR, and male sex.
Zhang and Bailey presented retrospective data on 294 (59 males) patients over
15 years of age who had been followed on average for more than 10 years. At
last follow-up, 24% had creatinine clearance <1.2 mL/s per 1.73 m2 [30].There have been
several other smaller long-term follow-up studies published. Mor et al.
reported data from 100 Israelis (79 women and 21 men) followed for more than 20
years post antireflux surgery [26]. In their cohort, only 1/100
patients had an abnormal serum creatinine level; however, eGFR was not reported,
no information on voiding dysfunction was reported and there was no information
on VUR grade. Given these limitations, this study indicates a low risk of
progression to ESRD for their cohort. Arze et al. presented data from 130
patients (16 male) identified in 1976 as having renal scarring as defined by
IVP or pathologic evaluation of renal tissue post nephrectomy [31]. In their cohort which was
followed for up to 240 months, 18% had, or developed, CKD as
defined by Cr >130 uM/L. Hypertension, proteinuria, and repeated UTI were associated with increased GFR.
Nakashima et al. followed 95 patients who had renal scar or grade III or higher
VUR and found that 3/995 developed ESRD and that 35% demonstrated renal
function deterioration [32]. In their cohort, bilateral
scarring, proteinuria >300 mg per day, diastolic hypertension, and low GFR
(mean 0.82 mL/s per 1.73 m2) were associated with increased risk of
deterioration of renal function.


## 7. Prevention of ESRD in Patients with VUR

Currently, there
is little evidence from prospective, randomized controlled trials to direct
therapies to prevent ESRD in patients with VUR. One goal of treatment is to try
to prevent recurrent episodes of pyelonephritis and renal scarring by treating
voiding dysfunction, surgically correcting VUR, using daily antibiotic
prophylaxis and treating episodes of pyelonephritis quickly and effectively [33] (see Figure 1). All patients should be completely evaluated and treated for
voiding dysfunction as part of the evaluation and treatment of VUR in order to
maximize bladder function and preserve renal function. Randomized controlled
trials that have tested the benefit of surgical correction of VUR or
prophylactic antibiotic treatment have not demonstrated either is more
efficacious in preventing renal scarring or the overall rate of recurrent UTIs [10, 11].
Critically, these studies did not have a control group that received only
observation. In one of these trials, the International Reflux Study in Children
trial, surgical correction of grades III and IV reflux did reduce the
occurrence of febrile UTI. Unfortunately, this did not correspond to a decrease
in new renal scars or an improvement in renal function in surgically treated
children [10]. Several recent reports have
questioned the utility of daily antibiotic prophylaxis [34–36];
however, it is important to note that the studies from Garin et al. [35] and [34] Conway et al. reported on few male
subjects and did not address high-grade VUR. Specifically, the Garin trial
excluded those with VUR grades IV and V, and the Conway
study included only 10 patients with
VUR grades IV and V. Another recent randomized prospective trial demonstrated a
benefit of  prophylactic antibiotics
versus observation in preventing positive surveillance urine cultures in asymptomatic
boys with grade III VUR [37]. In the near future, we will
hopefully have new data from a large, multicenter trial comparing daily
antibiotic prophylaxis versus observation in patients with low-grade reflux [38]. At this point in time, there
does not appear to be good evidence to support using daily antibiotic
prophylaxis to prevent UTI or renal scarring in patients with VUR grades I–III; nor is there
evidence that for grades III-IV VUR surgical
correction of VUR prevents new renal scarring compared to daily antibiotic
prophylaxis.  Because grade V VUR is
rare, there have not been any significant randomized, controlled, prospective
trials to evaluate treatment options. Thus, the treatments that may prevent
ESRD in this high-risk population are incompletely characterized. For patients
with high risk of progression to CKD and ESRD such as those with grade IV and V
reflux, significant renal scarring and those with reduced GFR, the surgical
correction of reflux and daily antibiotic prophylaxis should be strongly considered;
and risks and benefits of these treatments should be discussed with families.
In addition, close clinical follow-up and rapid treatment of episodes of pyelonephritis
should be instituted to preserve renal function and prevent progression to ESRD.Figure 1
Schematic representation of factors involved in progression to ESRD for patients with VUR. In the majority of patients with VUR, VUR resolves and the patients demonstrate normal renal function (green pathway). Some patients with renal scarring and/or who have recurrent pyelonephritis also retain normal renal function (green arrows). Other patients with VUR develop RN, proteinuria, and hypertension. In all cases, abnormal renal development can accompany RN and contribute to renal scarring, proteinuria, hypertension, and progression to CKD (solid black arrows). Prevention of ESRD focuses on intervening to prevent recurrent pyelonephritis (1), by actively evaluating and treating episodes of pyelonephritis to prevent renal scarring (2), and by treating hypertension (3) and proteinuria (4) to preserve renal function.


## 8. Hypertension and Proteinuria as Therapeutic Targets for Prevention of ESRD

Another aspect of
preventing the progression of RN to ESRD is the treatment of hypertension and
proteinuria, both of which are indicators of renal damage and contribute to ongoing
deterioration of renal function in many renal conditions. As described above,
multiple studies have demonstrated a correlation between RN and hypertension. Hypertension
has been shown to affect the rate of decline of renal function in other
conditions, thus controlling hypertension should be a significant goal for
treatment of patients with VUR.In addition,
multiple studies have demonstrated a correlation between proteinuria and risk
for CKD in RN. The magnitude of proteinuria associated with increased risk of
CKD or deterioration of function varies somewhat but even mild proteinuria
appears to be associated with increased risk for renal deterioration. El-Khatib
et al. showed an increased risk of
deterioration of renal function for patients with >0.2 G per day of
proteinuria with a progressively increasing risk of deterioration for patients
with >1 G per day of proteinuria [29]. Nakashima et al. demonstrated an increased risk for deterioration of renal function for patients
with >0.3 G/day of proteinuria [32]. Neild et al. also demonstrated
a correlation between increased proteinuria and elevated creatinine with patients
having a GFR of 0.25 mL/s per 1.73 m2 to 0.5 mL/s per 1.73 m2 having an average protein to creatinine ratio of
209 mg/mmol compared to 38 mg/mmol for those patients with GFR of 0.83 mL/s per 1.73 m2 to 1.0 mL/s per 1.73 m2 [24].Neild et al. also presented
the only data in VUR patients that ACE inhibitors may be able to slow the
progression of renal deterioration associated with severe RN [24]. One caveat to their finding
was that benefit of ACE inhibition was demonstrated only for those patients
with mildly reduced GFR of 0.83 mL/s per 1.73 m2 to
1.0 mL/s per 1.73 m2 [24]. There is evidence that in
nondiabetic patients with renal parenchymal abnormalities that ACE inhibition
reduces proteinuria and may help to preserve renal function [39–41].
Given the benefit of ACE inhibition in other renal conditions and the limited,
but promising, data presented by Neild et al. [24], ACE inhibitors and/or
angiotensin receptor blocking agents should be the first choice for controlling
hypertension and proteinuria and should be initiated early in the course of
disease. Furthermore, based on data from other nondiabetic renal disease, one
should use ACE inhibition and/or angiotensin receptor blockade even in the
absence of hypertension when a patient has VUR and proteinuria. Controlling
hypertension and proteinuria in patients with VUR should be considered standard
maintenance therapy for those with VUR and RN.


## 9. Conclusions

VUR is commonly
identified in pediatric patients and can be associated with reflux nephropathy,
CKD, and, rarely, ESRD. The progression of RN to CKD and ESRD is more likely in
patients with reduced GFR, bilateral VUR and/or renal scarring, grade V VUR,
proteinuria, and hypertension. Identification of patients with these clinical
characteristics should be the goal of clinical, biochemical, and radiological to evaluation of patients presenting with hydronephrosis on prenatal ultrasound or febrile UTI. Because progression
to ESRD is rare in VUR and often requires many decades to develop, there are
limited prospective, randomized, controlled trials available to direct therapy.
All patients should be evaluated and treated for voiding dysfunction, where
appropriate, and rapidly diagnosed and treated for recurrent pyelonephritis. Evaluation
and treatment of patients with VUR should be directed at preventing
pyelonephritis and new renal injury; however, there is little evidence that
either surgical correction of VUR or antibiotic prophylaxis prevents
pyelonephritis and new renal scarring in comparison to careful clinical
observation alone.  In addition, for
those patients who do develop RN, care should be taken to normalize blood
pressure and reduce proteinuria in order to preserve renal function. In the
future, with continued basic research, we may be able to develop pharmaceutical
therapies aimed directly at the molecular pathophysiology of RN to slow
progression of RN to ESRD. For now, we must provide the best supportive care to
patients to preserve renal function and prevent ESRD in patients with vesicoureteral
reflux and reflux nephropathy.



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