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NDT Advance Access originally published online on June 4, 2006
Nephrology Dialysis Transplantation 2006 21(9):2491-2497; doi:10.1093/ndt/gfl216
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

Outcome of kidneys in patients treated for vesicoureteral reflux (VUR) during childhood

Tuija Lahdes-Vasama1, Kaija Niskanen2 and Kai Rönnholm3

1 Paediatric Research Centre, Tampere University, Division of Paediatric Surgery, Tampere University Hospital, 2 Helsinki Medical Imaging Centre 3 Division of Paediatric Nephrology Hospital for Children and Adolescents, Helsinki University Central Hospital, Finland

Correspondence and offprint requests to: Tuija Terhikki Lahdes-Vasama, Tampere University Hospital, os 9B, BOX 2000, 33521 Tampere, Finland. Email: tuija.lahdes-vasama{at}pshp.fi



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Outcome of renal function and blood pressure (BP) at early middle age was clarified in patients treated for vesicoureteral reflux (VUR) during childhood.

Methods. Information of renal function was available from 147 (55%) of 267 patients treated for non-obstructive VUR of any grade. Twelve patients had died of kidney-related conditions and eight had gone into terminal uraemia. A total of 127 patients participated in the study.

Results. The mean age of the participants was 41 years. No signs of renal scars were detected by ultrasound examination in 53 (42%) subjects. Unilateral scarring was seen in 44 (35%) and bilateral in 30 (24%) subjects. Glomerular filtration rate (GFR) showed moderate or severe renal insufficiency in four (3%) participants, all with bilateral scars. Normal GFR was found in one-third of the patients. Twenty-five (83%) subjects with bilateral scars and 60 (62%) of the other participants had abnormal GFR values (P < 0.05). Proteinuria was found in 12 (9%) and albuminuria in 30 (24%) participants. Hypertension was diagnosed earlier in 14 (11%) patients, eight having bilateral scarring (P < 0.01). Diastolic BP was significantly lower in subjects without scars compared with those having scars in one or both kidneys (P < 0.05).

Conclusions. Renal function was slightly lowered in more than half of the participants. Findings of the participants with unilateral scarring or unscarred kidneys were similar, except for the increased tendency for hypertension in subjects with scars. A total of 83% of the patients with bilateral kidney scars had lowered kidney function, a quarter presented with proteinuria and a half with hypertension. Long-term follow-up for all the patients with earlier VUR is emphasized.

Keywords: hypertension; kidney scars; long-term; renal function; vesicoureteral reflux



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Clinical implications of kidney scarring associated with childhood urinary tract infection (UTI) and vesicoureteral reflux (VUR) vary from normal renal function and normotensive state to fatal end-stage kidney disease and hypertension [1]. Hypertension due to nephropathy tends to be a progressive disease impairing renal function [2,3]. Hence, studies with a very long follow-up time are needed to delineate future prospects of these patients.

Although prospective studies are more accurate than retrospective ones, they are difficult to accomplish when the follow-up time is planned for decades. In earlier studies, the follow-up time of patients with childhood VUR has varied from 5 to 27 years [4–6]. Some good long-term studies on patients with renal scarring include cases with childhood pyelonephritis without VUR [4]. Subjects with grades 1–2 VUR are excluded from most of the studies, although renal scarring, hypertension and chronic renal insufficiency have also been associated with the mildest forms of VUR [6,7].

We wanted to explore the kidney outcome in a cohort of patients with childhood VUR of any grade at their early middle ages. We divided the patients into three subgroups based on whether they had ‘no scars’, ‘unilateral scars’ or ‘bilateral scars’ to see a possible difference between scarring and clinical findings.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
The Ethical Review Committee at the Helsinki University Central Hospital (HUCS) approved this study. Names, birth dates and old health reports were found of 267 (58 men) consecutive patients, who had been diagnosed for primary non-obstructive VUR (without ureteral or bladder outflow obstruction or neurological pathology), at the Children's Hospital in Helsinki between 1955 and 1965 (Table 1). Cases with double ureter systems were included. Twenty-three patients (8.6%) had died, 12 (4.5%) due to kidney-related conditions. Eight patients (3.0%) who had either undergone kidney transplantation (seven) or were on dialysis (one), were not invited. A total of 191 (72%) patients, of whom 44 (23%) were males, were traced and an invitation letter delivered. Finally, from 1996 to 2001, 127 (66%) of the invited subjects participated in the study, which included laboratory tests, a renal ultrasonography (US), measurements of weight, height and blood pressure (BP) and finally subjects were interviewed in regard to general health, medication and surgery. The study group consisted of 113 women and 14 men with a mean age of 41 years (range 33–55 years) and with an average of 37 years (range 27–48) of follow-up time. VUR was diagnosed at a mean age of 4.3 years (range 3 months – 16 years), median ages being 3.3 years for females and 2.0 years for males. The condition had been bilateral in 68 (54%) children (8 males). Out of 109 patients (31 males), whom we could not trace or who were non-responders, 20 (7 males) had bilateral disease including two with childhood nephropathy (one of each gender). VUR was only graded as ‘dilating’ or ‘non-dilating’ according to the cystogram reports; a ‘dilating’ VUR was found in 83 (65%) patients. Indication for a cystogram was at least one, but usually recurrent, febrile urinary tract infections. Also, reports of urograms for all patients were reviewed to exclude obstructive conditions. A neurogenic bladder and urethral obstruction were ruled out with a cystoscopy in half of the patients. Two patients had a solitary kidney and in 21 patients VUR was associated with a double system. Operative treatment was given to 43 (34%) patients at a mean age of 5.5 years (range 0.5–25). Indications for operative treatment varied; usually the most severe cases were operated on. A re-operation was needed for two patients due to ureteral obstruction and for six patients, because of severe residual reflux. Later, three nephrectomies and four heminephrectomies were performed for non-functioning kidney tissue (Table 2). About 66% of the patients had conservative treatment: a follow-up with or without prophylactic anti-biotherapy (nitrofurantoin or sulpha) for various time periods. Reflux disappeared spontaneously in 32 (38%) of these patients during childhood and was found persistent in eight (10%) patients in adulthood. In 43 (52%) patients, VUR was still seen in childhood or in adolescence, but the follow-up was discontinued, because the grade of VUR was non-dilating and the patients were well.


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  		Table 1. Details of the 267 consecutive patients whose VUR was diagnosed at the Children's Hospital in Helsinki between 1955 and 1965

 

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  		Table 2. Characteristics and operative treatment of VUR in the study patients

 
All the patients underwent an ultrasonography as follows: 72 patients were examined with ATL 5000 (Advanced Technology Laboratory, 1998) using a convex C5-2 MHz convex probe, 46 patients with ATL 3000 (1996) using C7-4 MHz convex and P2-3 phased array probes, nine patients were examined with Acuson 128XP/10M (1993). Any suspicious finding in the ultrasound examination (as was the case in 82 patients) led to a further imaging, which was performed in 77 (94%) subjects as follows: urogram in 65, Technetium-99m-dimercaptosuccinic acid renal scintigraphy (DMSA) in 63 subjects. All the patients were divided into subgroups of ‘no scars’, ‘unilateral scars’ and ‘bilateral scars’. A patient who had undergone a removal of renal tissue for scarring was classified as having a scar on the operated side.

Blood and urine samples were obtained after an overnight fasting from each participant between 8 and 12 am. The analyses for blood/serum samples included (normal range in parentheses) haemoglobin (135–180 g/l for men, 125–160 g/l for women), creatinine (<115 µmol/l for men, <110 µmol/l for women), urea nitrogen (6.4–12 mmol/l), potassium (3.7–5.3 mmol/l), sodium 137–149 (137–149 mmol/l), calcium ion (1.15–1.32 mmol/l), phosphate (0.8–1.4 mmol/l) and rennin (2.0–5.0 µg/l/h). The analyses for urine included sodium, potassium, calcium, phosphate, and also creatinine (crea), albumin, protein and ß-2-microglobulin. To evaluate tubular damage, we measured the excretion of sodium, potassium, calcium, phosphate and ß-2-microglobulin in relation to creatinine excretion in the urine spot samples. To evaluate glomerular damage, we measured total protein and albumin excretion in relation to creatinine excretion in the urine spot samples. Excretions were calculated for urine creatinine and the reference values used were for sodium: <28 mol/mol crea, potassium: <13 mol/mol crea, calcium: 0.04 – 0.7 mol/mol crea, phosphate: 0.8–2.7 mol/mol crea, albumin: <2.26 mg/mol crea, total protein:<20 g/mol crea and ß-2-microglobulin: <0.04 g/mol crea. Glomerular filtration rate (GFR), as millilitre per minute, was calculated using Cockcroft–Gault formula [(140 – age (years) x weight (kg)/(0.0113 x plasma creatinine x 72)] [8]. This value was multiplied with 0.85 for females. GFR was corrected per 1.73 m2 body surface area. Kidney function was regarded as normal or mildly reduced, when the result was at least 60 ml/min/1.73 m2. Results were referring to moderately or severely impaired function when the value was 30–59 and 15–29 ml/min/1.73 m2, respectively. Those who scored <15 ml/min/1.73 m2 were regarded as suffering from terminal uraemia [9].

The BP was measured from both arms after 15 min in sitting position. The mean values were recorded and the standard deviations were calculated [10]. The subjects on anti-hypertensive medication were excluded from the measurements.

The differences in abnormal findings between the groups were analysed by chi-square test. Parametric results of the groups were compared using unpaired t-test.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Scarring of the kidneys
Ultrasonography examination of the kidneys revealed no signs of scars in 53 (42%) patients. All these kidneys were well grown (≥–1.0 SD) except for one, which was small (–2.0 SD). Scarring was identified unilaterally in 44 (35%) subjects including two women with a solitary kidney. Both kidneys were found scarred in 30 (24%) participants (Table 1). Table 2 shows how many patients, classified according to their kidney scars, had had unilateral or bilateral VUR, double ureters or operations. Two-thirds of the patients with bilateral scars had been operated on.

The kidney function
From the initial 267 patients, 8% had died of kidney-related diseases and 3% had gone into terminal uraemia. The laboratory findings for the kidney function of the study participants are presented in Table 3. Abnormal values for plasma creatinine were found only in five subjects with bilateral scarring (4%) whereas values for plasma urea nitrogen were above the normal range in 14 (11%) patients. GFR was normal (≥90 ml/min/1.73 m2) only in 33% of the patients. Normal GFR values were seen significantly less often (P = 0.0335) among subjects with bilateral scars than among the rest of the participants. Moderate or severe renal insufficiency was found only in the subgroup with bilateral scars (3%). There were no significant differences in mean blood haemoglobin concentrations between the subgroups.


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  		Table 3. Laboratory findings for the kidney function of the study patients. GFR is calculated from Cockcroft–Gault formula and corrected per 1.73 m2 body surface area [8]

 
Tubular and glomerular function
The results referring to tubular and glomerular function are shown in Table 4. High excretion of sodium and potassium was found in 6 and 3% of the patients, respectively. Fractional excretion of sodium was below 1% in 14% of the patients. Calcium excretion was high only in 5% of the patients. On the other hand, the excretion of phosphate was high in 41% of the patients. The mean plasma ionized calcium was quite low (1.19 mmol/l) and 17% had values lower than normal. Only two patients (2%) had ß-2-microglobulin excretion higher than normal. Both patients had bilateral scars. There was no statistical difference in these values between the subgroups. Total protein excretion was higher than normal in 9% and albumin excretion was higher than normal in 24% of the patients. Patients with bilateral scars had higher urinary protein (P = 0.0029) and albumin (P = 0.0157) excretions than the other two groups, which again did not differ much from each other.


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  		Table 4. Laboratory findings for renal mineral and protein excretion, where excretion of a substance = value of substance in urine/value of creatinine in urine and fractionated sodium U-FrNa (%) = U-Na/U-creat x S-Na/S-creat x 100%. The number of patients with abnormal values is shown

 
Blood pressure
Measurements of the BP of the study patients excluding those on anti-hypertensive drugs are presented in Table 5. Hypertension was diagnosed earlier in 14 (11%) patients. Subjects with bilateral renal scarring had the diagnosis made significantly (P = 0.0073) more often than the others. In addition, 22% of the study group had either systolic or diastolic BP readings over +2 SD. About 29% of the patients had either systolic BP >140 mmHg or diastolic BP >90 mmHg. Diastolic BP was significantly lower (P = 0.0106) in patients without scars compared with those with scars in one or both kidneys. There was also a significant difference (P = 0.0266) in diastolic values between the no scar and unilateral scar groups. The same significant difference was seen in diastolic SD values (P = 0.0124). Mean values for plasma rennin did not differ between no scars, unilateral and bilateral subgroups (2.1, 1.8, 1.6 µg/l/h, respectively); abnormal values were found only in five (4%) patients.


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  		Table 5. Systolic and diastolic BP and number of patients with abnormally high values or with BP medication in different subgroups

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
General
Lifelong follow-up studies are needed for such a progressive disease as reflux nephropathy to delineate risk of hypertension and renal insufficiency in youth, middle age and in old age [1–3]. Prospective studies are more accurate than retrospective ones, but when the follow-up time is planned for decades, it takes a clinician's active lifetime to get the final results. Earlier research groups have reported studies where mean age of the participants was <30 years [4–6,11]. Many informative long-term studies on kidney scars are based on patients who have suffered from childhood pyelonephritis, but only some of them have had VUR [4,6]. Also, some long-term follow-up studies have excluded male patients or have concentrated only on results of operated patients [5]. Usually patients with VUR of grades 1–2 are also excluded, although hypertension and chronic renal insufficiency have also been associated with the mildest forms of VUR [7]. We wanted to explore the kidney outcome in a cohort of patients in early middle age, an age where diseases like diabetes, idiopathic hypertension and arthritis, which possibly have a direct or indirect effect on renal function, start to appear. In order to achieve this goal, we organized this retrospective study with more than a 3 decade follow-up time. The study included patients with any grade of VUR and also those with double ureters to cover the whole spectrum of the disease. Between 1955–1965, there was only one children's hospital in Finland, which diagnosed and treated all the patients with VUR. During that time period VUR was not, however, systematically investigated after every febrile UTI. There are some problems in examining the cause of VUR: half of the patients went through a cystoscope to rule out a neurogenic bladder, but otherwise bladder dysfunction was not studied at that time period. Additionally, all patients went through repeated cystograms and urographies, but we do not have enough information from the old imaging reports to tell if the present renal abnormalities are caused by febrile UTIs or if they are findings of a dysplastic kidney. There were no problems in our country to find out the exact number of patients on dialysis or with transplanted kidneys or to clarify a patient's cause of death. We could clarify the kidney outcome for 55% of the earlier patients. This figure is fairly good considering our exceptionally long follow-up time. The longer the follow-up time is, the larger the number of patients who are lost at the time of check-up. This problem will probably be more prevalent in the future due to increased mobility of populations. Male patients were not as willing to participate in the study as females; the percentage of the male patients was 22 at diagnosis, but only 11 at the follow-up examination. This may affect the results. In other follow-up studies, the relative proportion of male participants has been larger, varying from 16 to 27% [3,6,7,11,14]. Those patients who were missing from our study, however, had had mostly (83% of the females and 77% of the males) a unilateral disease.

Imaging findings
Sensitivity of ultrasound examination in the detection of renal scars has been controversial. Roebuck et al. [12] reviewed available studies and concluded that the sensitivity appears to be acceptable in children. It is probable that we have missed some minor scars when we used US for screening in our study instead of DMSA. However, when examining adults whose scars date back to childhood disease, it is hard to believe that the normally grown, smooth kidneys with normal-looking parenchyma would contain significant scars. Furthermore, US is a relatively convenient test lacking venous puncture and radiation. Hence, we based our classification of scars/no scars on ultrasound findings and in 94% of the patients with abnormal findings, the scars were confirmed with further imaging. Renal scars were found even in 58% of the patients whose kidney outcome was clarified. Other research groups have published lower rates for renal scars; Smellie et al. [6] found scars in 44% of their patients with severe VUR, and Cooper and Atwell [5] found unilateral scars in 32.5% and bilateral scars in 16.9% of the girls who were operated on for VUR in their childhood. Our rate of 58% for renal scars is surprisingly high considering that also the mildest grades of VUR were incorporated into the study and that the imaging was primarily performed with ultrasound. Probably the difference between our and other studies is explained by ineffective treatment of urinary tract infections and VUR in the early sixties. Bailey et al. [13] presented the outcome of 21 patients after a mean of a 24 year follow-up: only four (19%) patients had normal kidneys, but the study included only those with gross childhood VUR. Also, recently Olbing et al. [14] reported 10 year follow-up results of a prospective trial of 223 patients with severe VUR. Unscarred kidneys were found on urography only in 38% of these pubertal children. Because our study patients might have had multiple febrile UTIs before their first cystography, their kidneys are probably more scarred than those of modern patients in whom VUR is diagnosed earlier. Nowadays, cystography is more often performed early because of hydronephrosis seen in antenatal US and prophylactic anti-biotherapy started in cases of VUR. It seems that there have been some risk factors which led to bilateral scarring. Table 2 shows some differences between the three groups: patients who have bilateral scars had had bilateral VUR twice as often as those in the other groups, their VUR had been classified more often as ‘dilatated’ and they were operated on at least twice as often as the other patients. Also, every fifth operation had been unsuccessful in this group, which is considerably more than in those with unilateral scars (7%) or no scars (0%). There was no difference between the groups in mean age at follow-up, but mean age at diagnosis was 1 year lower in the group of bilateral scars (3 years) than that in the other two groups (4 years).

Renal function and excretion/concentration
Reflux nephropathy is complicated by persistent proteinuria, progressive renal insufficiency and hypertension [1]. From our cohort of 267 subjects, 20 (7%) had died of kidney-related conditions or gone into terminal uraemia. The figures are slightly higher than in other studies with shorter follow-up time [6]. Three of 30 patients had developed end-stage renal disease in a study of Jacobson et al. [4] with all patients having renal scars 22–41 years after childhood pyelonephritis.

To evaluate renal clearance function of the participants, the Cockcroft–Gault formula was used. This method gave us an unexpectedly small amount of patients with normal renal function: only 42% of the patients without scars and 32 and 17% of those with unilateral or bilateral scars, respectively. According to Davies and Shock [15], renal function also may be lowered with the normally grown kidneys and with the apparently normal parenchyma. This is more evident by age when parenchyma gets older and a natural decrease of GFR occurs. Mild kidney damage (GFR 60–89 ml/min/1.73 m2) was found in 64% of the patients. Moderate or severe renal insufficiency (GFR <30 ml/min/1.73 m2) was found in one patient with scars in both the kidneys. Jacobson et al. [4] found that after a mean of 27 year follow-up time, 10% of their patients with childhood pyelonephritis and focal scarring had a GFR <30 ml/min/1.73 m2. The study included only 30 of 53 patients, which might imply a highly selective group. A prospective study where 54 females, with renal scars due to childhood pyelonephritis, were followed for a median of 15 years showed that only seven (13%) presented with a lowered GFR of 70–90 ml/min/1.73 m2 [16]. A relatively short follow-up time may explain the better results.

VUR and pyelonephritis may damage the tubulus and glomerulus function. Marks of impaired tubulus function include decreased mineral and small protein re-absorption and proteinuria can be a mark of glomerulus damage. Spot urine samples were used for testing kidney mineral and protein excretion. There are few recommended normal values for spot urine mineral and protein concentrations. As cut-point values for abnormal excertion, we used values found in the literature and in an article by Ardissino et al. [17]. Tomlinson et al. [18] claimed in their study of 133 children with VUR that tubular dysfunction is common in children with bilateral renal scarring. They also concluded that the tubular damage due to relative nephron hyperperfusion precedes glomerular protein leak. After a follow-up of 28 children with reflux nephropathy, Konda et al. [19] found that elevated levels of {alpha}-1-microprotein may predict risk of lowered renal function even before appearance of significant proteinuria.

In our study, there were no clear signs of impaired tubulus function measured by urinary mineral and ß-2-microglobulin excretions. The mean values of urinary excretion of sodium, potassium and calcium were normal, and there were no differences between the subgroups. Fractional urinary excretion of sodium was high in 14% (10% of those without medication affecting sodium excretion) of the patients. This may reflect higher sodium intake in these subjects rather than impaired tubular re-absorption. Also, medication with effect on sodium excretion was taken by 12 patients, six of them belonging to the subgroup with bilateral scars, four in the group with unilateral scars and two in the group without scars. Of these subjects, increased sodium excretion was found in four, zero and two, respectively. Phosphate excretion was high in 41% of the patients. This may reflect insufficient calcium intake, because plasma calcium concentration was low in many subjects. Urinary ß-2-microglobulin excretion was high only in two patients with bilateral scars. Others had normal excretion. This is less than in the study of Smellie et al. [6] where they found high urinary ß-2-microglobulin excretion in 13 of 162 patients, although in average their patients were younger than ours and severity of VUR was similar to that found in our study. About 9% of the patients had proteinuria and 24% had albuminuria. Proteinuria and albuminuria were more prominent findings in subjects with bilateral scars (23 and 40% respectively, P = 0.0029 and P = 0.00157) than in other subjects. Thus, children with VUR and bilateral scars are more prone to have glomerular damage.

Reduced mass of functional renal tissue (in agenesis, hypoplasia, nephrectomy or heminephrectomy) may cause overload to the rest of the kidney [20]. Seven of our patients (11% of ‘unilaterally scarred’) had reduced renal mass, with the rest of the tissue being normal. Five of them had lowered renal creatinine clearance, two had diagnosed hypertension and one presented with albuminuria. So it seems that low GFR in these people was related also to the size of the kidneys, a phenomenon, which was also suspected by Berg [21]. The absent tissue, however, probably does not have any effect on BP.

Hypertension
Eleven percent of the study population was on anti-hypertensive medication. As expected, a great majority of these patients had scars in their kidney(s). Diastolic BP was significantly lower in patients without scars compared with those with scars in one or both kidneys. In addition, 22% of the study patients had either systolic or diastolic BP expressed as SDs >+2.0 [10]. Also, 29% of the non-medicated study subjects had either systolic BP >140 mmHg or diastolic BP >90 mmHg. These subjects had BP figures, which may reflect risk of hypertension. However, the prevalence of hypertension in this age-group in Finland is 56–60% in men and 43–49% in women [22]. Thus, it seems that the prevalence of hypertension in the study group did not differ from the normal Finnish population. Smellie et al. [6] reported hypertension only in 4% of their VUR patients, whose mean age was 27 years, most of them having bilateral scarring. Cooper and Atwell [5] found similar results in surgically treated girls in their twenties. Nielsen et al. [11] reported that in their study including 51 conservatively treated patients with any grade of VUR in childhood, only two presented with borderline hypertension. The participants of these studies were on average 14–20 years younger than ours. Gower [2] found hypertension in 11 and 28% of his patients with unilateral and bilateral renal scarring, respectively, at a mean age of 41 years, which was consistent with our findings. High prevalence of hypertension among patients without scarring is probably also connected to the age of the patients.

Although modern management of VUR and urinary tract infections will improve the prognosis in the future, there is a need for long-term follow-up. Patients with scars in both their kidneys should probably be followed and tested throughout their lifetime. In our study, hypertension of this subgroup was well diagnosed and treated. About a third of those with unilateral scars, however, had suspicion of hypertension. Because two-thirds of the patients with unilateral scars and almost half of the subjects without signs of scars are presented with mild or moderate renal function, these patients should be evaluated for BP and provided with information about kidney-sparing lifestyle at suitable intervals.



   Acknowledgments
 
The authors thank the specially trained nurses Eija Satukangas, Merja Oksanen, Pirjo Nurmi and Leila Uusitalo for the essential help in arranging the examinations for the study patients and the Finnish Research Foundation of Pediatric Diseases for financial support.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 17.11.05
Accepted in revised form: 29. 3.06


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