Chronic pyelonephritis was the first term coined to describe permanent residual renal lesions observed in children with a history of one or more febrile urinary tract infections (UTIs).1 In the 1960s, evidence emerged of a potential association between chronic pyelonephritis and vesicoureteral reflux (VUR), which motivated the diffusion of a new term, reflux nephropathy.2 This new concept, initially based on radiological findings, referred to an association between VUR, renal scarring and the possibility of developing chronic renal disease,3 although little attention was given to the presence of other associated renal functional defects. In the late 1990s, avoiding this term was recommended, as it was established that sterile VUR did not cause scarring,4 and that infection of the renal parenchyma, rather than VUR, was the necessary condition for its development,5 which means that VUR is not the actual cause of the scarring, but rather the acute inflammation of the renal parenchyma.4–7 Thus, acquired renal scarring was proposed as an alternative to replace the term reflux nephropathy.8 However, the new term underemphasised congenital defects (dysplasia, hypodysplasia) that may be associated with VUR and that have come to be known as congenital reflux nephropathy.8,9

Preliminary studies have shown that VUR interferes with renal tubule function. Thus, a reduction in renal concentrating ability10,11 and an increase in the urinary excretion of albumin12 and of N-acetyl-β-glucosaminidase (NAG)13 have been reported.

We designed a study to assess whether the abnormalities observed in basic renal function tests were different when VUR was active versus, once VUR had resolved, only the residual congenital or acquired loss of renal parenchyma remained.

At the time of diagnosis, imaging findings were abnormal in 52 children: renal dysplasia (n=14), an area of unilateral scarring (n=14), several areas of scarring (n=11), mild isolated hydronephrosis (n=7), moderate-severe isolated hydronephrosis (n=1), duplicated collecting system (n=4) and renal agenesis (n=1). In addition, in 14 children, the acute-phase 99mTc-DMSA renal scan revealed areas of reduced tracer uptake characteristic of acute pyelonephritis. Renal imaging findings were normal in the rest of cases (n=23). Of the 14 children with renal dysplasia, 10 were male, 8 had grade IV VUR, and 6 had grade III VUR.

At the end of followup, 19 patients had unilateral renal scarring (one of them had a duplicated collecting system) 16 had several areas of scarring, 14 had a dysplastic kidney, as mentioned above, and 9 renal atrophy; one patient had renal agenesis. Renal morphology was normal in the 30 remaining children (3 with a duplicated collecting system). In short, 59 patients had a decrease in renal parenchyma of varying degree and 30 had an apparently intact renal parenchyma.

Table 1 presents the qualitative analysis of the renal function parameters in the patients, grouped by the grade of VUR a baseline, at diagnosis and at the end of followup. We found statistically significant differences in the UOsm, which at the time of diagnosis was decreased in 21% of children with mild VUR, 37% of children with moderate VUR and 67% of children with severe VUR. At the end of followup, we found a statistically significant difference in the frequency of patients with an elevated albumin/creatinine ratio based on the grade of reflux: none with mild VUR, 10% of children with moderate VUR and 39% of children with severe VUR (Table 1).

Using the data presented in Table 1, we analysed diagnostic performance parameters to compare the findings in severe VUR versus mild to moderate VUR in both timepoints under study (Table 2). The maximum UOsm had a sensitivity of 66.67% for discrimination of both types of VUR, which dropped to 18.18% after VUR resolved. The sensitivity of the other 2 parameters at the time of diagnosis was low. Once VUR had resolved, the specificity of both the maximum UOsm and the albumin/creatinine ratio was greater than 90%, and the specificity of the NAG/creatinine was 100%. The odds ratio was statistically significant for the maximum UOsm and urinary albumin at both timepoints (Table 2).

Table 3 presents the results of the quantitative and qualitative analysis of renal function parameters in the initial timepoint (at diagnosis of VUR) and at the end of followup (resolved VUR). We found significant differences in the quantitative values of the 3 parameters under study. At diagnosis, 46% of children exhibited a decreased concentrating ability, 18% an increased albumin/creatinine ratio, and 20% an increased NAG/creatinine ratio. At the end of followup, the renal concentrating ability (maximum UOsm) was decreased in only 9% of patients, and the albumin/creatinine ratio increased in 15%. The NAG/creatinine ratio was normal in every patient with resolved VUR (Fig. 1). Of the 8 patients with an impaired renal concentrating ability at the end of followup, 7 (87%) exhibited a decrease in renal parenchyma (Table 3).

Figure 1.

Bar chart representing the proportion of patients in the normal and abnormal range for the 3 analysed renal function parameters at the time of diagnosis of VUR and at the end of followup (data shown in Table 3).

Alb, albumin; Cr, creatinine; NAG, N-acetyl-β-d-glucosaminidase; ns, not significant; UOsm, urinary osmolality.

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At the end of followup, when we grouped patients based on whether or not they exhibited a decrease in renal parenchyma, the frequency of patients with an increased albumin/creatinine ratio was higher in the group with decreased renal parenchyma (Table 4).

We did not present the estimated glomerular filtration rate (eGFR) calculated with the updated Schwartz formula (2009) in any of the tables. Only 3 patients had an eGFR of less than 90mL/min/1.73m2 at the end of followup; two of them exhibited a decreased concentrating ability and an increased creatinine/albumin ratio.

Many patients in the study were managed at a time when the approach to treatment was different from the current one. Children with VUR that had undergone renal function tests seemed to have the poorest outcomes. For this reason, the frequency of surgical management (endoscopic or open surgery) was higher compared to what is usually observed in hospitals in Spain, and the frequency of scarring at the end of followup was higher compared to longitudinal studies on the subject, which reported an incidence of new scarring of approximately 10%.18,19

As we mentioned in the introduction, chronic pyelonephritis was the first term used to describe residual lesions that appeared after one or more febrile UTIs.1 Today, it may seem difficult to understand why renal lesions found in the forensic examination of children would contain bacteria by areas of fibrosis and nephron loss; features also observed in animal models of UTI, and this could be due to the lack of effective antibiotics in the beginning and the fact that the agents could not penetrate the scar tissue.20 The persistent presence of bacteria suggests that a residual bacterial population could remain in the renal parenchyma and pelvis for a period of time after a febrile UTI and could cause recurrence in some patients.

As we already mentioned, the apparent association of chronic pyelonephritis and VUR was labelled reflux nephropathy.3 This is a radiological construct that translate to a decrease in renal parenchyma and that is confusing for several reasons. On one hand, renal development anomalies characterised by a decrease of renal parenchyma (dysplasia and hypoplasia) overlap with VUR; renal dysplasia is usually associated to massive VUR, most frequently unilateral and in male patients.8,9 Renal dysplasia is not caused by vesicoureteral reflux in isolation, but rather results from the association of 2 congenital anomalies of the kidney and urinary tract (CAKUT), which is relatively common in humans. In one of the best published editorials on the subject, Fernández Menéndez and Málaga Guerrero21 wrote that the term reflux nephropathy is misleading and that “this inadequate and confusing expression is still used today all too frequently. We will be able to completely eradicate its use once we stop being confused.” On the other hand, as we noted in the introduction, the necessary condition for development of renal scarring after a febrile UTI is inflammation itself and not the presence of VUR.4 At the end of the 1950s, Shapiro et al.6 demonstrated in an experimental study in rats without VUR that induction of pyelonephritis in the animals produced an inflammatory response that eventually led to scarring.20 In this sense, scarring is a loss of renal cortical parenchyma with secondary fibrosis resulting from the immune response to bacterial invasion, independently of the presence or absence of increased pressure in the urinary tract.22 Thus, it is well established that VUR is not the ultimate cause of scarring.4–7,20,23 However, a higher risk of renal scarring has been described in patients with VUR and urinary tract dilation.24 Knowing that VUR is not a necessary condition for scar tissue formation, it is reasonable to explore why the severity of VUR may be associated with an increased risk of scarring. A possible explanation would be that pyelonephritis in patients with VUR and urinary tract dilation may be caused by bacteria that are more virulent for yet unknown reasons.25,26

As concerns basic renal function tests, an experimental study in dogs published in the 1960s found a decreased renal concentrating ability after causing ureteral blockade.27 Later, when desmopressin became available, researchers were able to measure the maximum UOsm, which turned out to decrease in patients, both paediatric and adult, with pyeloureteral obstruction.28 Since then, a few studies have described an association between VUR and a decreased renal concentrating ability.10,11,29

In recent years, the renal mechanisms that explain the changes in water excretion in patients with increased pressure in the urinary tract have been investigated. Thus, studies have study found decreased activity in sodium transporters in the tubules,30 decreased expression of urea transporters31 and reduced aquaporin activity in the collecting duct.30 Specifically, an experimental animal model of VUR found a decreased expression of aquaporins 1 and 2.32 All these functional changes promote the development of polyuria and salt wasting.

In this regard, in our sample a decreased concentrating ability was the most frequent functional impairment in patients with active VUR (Tables 1–3; Fig. 1), and it was more pronounced in patients with high-grade VUR (Table 2). Thus, a decreased maximum UOsm as the most frequent functional abnormality in patients with what we could call true reflux nephropathy. However, once VUR had resolved, the concentrating ability (maximum UOsm) improved (Table 2) and the number of children with impaired concentrating ability decreased from 46% to 9% (Table 3; Fig. 1). Of the 8 children with persistently decreased concentrating ability, 7 had some form of detectable renal parenchymal damage (Table 3).

There is evidence that supports that an increase in urinary albumin excretion is an early sign of glomerular damage in both diseases without nephron loss (diabetic nephropathy, obesity) and with a reduction in the number of nephrons, in addition to a good predictor of future cardiovascular disease. An increase in urinary albumin excretion has been described in patients with VUR,12 but it is unclear whether this is due to the reduced renal parenchyma or to the increased pressure in the urinary tract.

In our case series, albuminuria was the most frequently observed abnormality in children with parenchymal loss once VUR had resolved (Table 3). Furthermore, patients that had more severe VUR at diagnosis had higher concentrations of albumin in urine at the end of followup (Tables 1 and 2) in association with the concomitant loss of renal parenchyma.

As for NAG, since the 1960s it is known that it originates from renal tissue,33 as it is found in the lysosomes of proximal tubule cells; when these cells are damaged, it is released to the tubular lumen, resulting in its increased urinary excretion.34 At first, it was used to assess the nephrotoxicity of aminoglycoside antibiotics, but NAG levels can also be elevated in patients with increased intratubular pressure, which is the case of urinary tract obstruction35 and VUR.13 There is debate as to whether this increase in urinary NAG excretion is due to an increased pressure or to a decreased glomerular filtration rate.12 In our sample, we found an increased urinary excretion of NAG in 20% of patients with active VUR that was probably secondary to increased pressure, as NAG levels normalised in all patients once VUR had resolved, which translates to a specificity of 100% (Tables 1–3, Fig. 1).

In short, from a functional standpoint, reflux nephropathy reflects a real process and applies when VUR is active, mainly translating into a decreased renal concentrating ability. On the other hand, albuminuria is the most frequent abnormality present in acquired renal scarring (once VUR has resolved), which is associated with the residual parenchymal damage. Although these 2 renal diseases are closely related, they should not share a name because they cause different functional abnormalities in different morphological contexts, that is, when VUR is active and when it is cured. Lastly, we propose the term dysplastic-scarring nephropathy as a more fitting alternative to acquired renal scarring in patients with cured VUR, loss of renal parenchyma and impaired renal function.

In addition to its retrospective design, one of the limitations of this study was that morphological evaluations and/or renal function tests were not carried out in some of the patients at both timepoints.

The authors have no conflicts of interest to declare.