Renal growth in children with severe vesicoureteral reflux: 10-year prospective study of medical and surgical treatment: the International Reflux Study in Children (European branch).

PURPOSE: To determine whether medical or surgical treatment better promotes renal growth in children with severe vesicoureteric reflux (VUR) and to examine factors influencing renal growth. MATERIALS AND METHODS: Three hundred two children younger than 11 years with urinary tract infection and grade III or IV VUR were randomly assigned to surgical (n = 149) or medical (n = 153) treatment and were followed up at serial intravenous urography for up to 5 years; 223, for up to 10 years (surgical, n = 110; medical, n = 113). Renal size was measured planimetrically on serial intravenous urograms and was related to the virtual height of L1 through L3 by expressing it as an SD score. RESULTS: There was no significant difference in mean renal growth between patients treated surgically or those treated medically after 5- or 10-year follow-up. Bilateral renal size of 80 surgical and 75 medical patients remained within 1 SD score. In patients entering the study at 2 years of age or younger and in those with grade IV VUR, bilateral VUR, or renal scars, there was a trend toward improved renal growth in those treated medically, but this finding was not statistically significant. When renal scarring or thin parenchyma was unilateral, the affected kidney grew less well, irrespective of treatment. Bilateral renal scarring was usually asymmetrical, with a corresponding effect on renal growth. CONCLUSION: There was no significant difference in renal growth during 10 years between surgical and medical treatment in patients with severe reflux.

Incidence of microalbuminuria in children with pyelonephritic scarring.

There is experimental evidence that loss of renal parenchyma results in hyperfiltration in the remnant glomeruli followed by development of glomerulosclerosis. Microalbuminuria, i.e., a urinary albumin excretion rate of 20-200 micrograms/min, is considered to be an early predictor of diabetic glomerulosclerosis. Hypothetically, increased urinary albumin excretion in patients with pyelonephritic scarring may also indicate glomerulosclerosis, with risk for future deterioration of renal function. This study was performed to determine the incidence of increased albumin excretion in children with mild to moderate pyelonephritic scarring, and to relate the information to glomerular filtration rate (GFR; clearance of inulin) and effective renal plasma flow (clearance of para-aminohippuric acid), as well as to the degree of scarring. The functional investigations were performed under water diuresis. Fifty-seven children, aged 1.7-17.9 years, with pyelonephritic renal scarring were included in the study. Nine young healthy adults were used as controls. The GFR was significantly lower in the children with pyelonephritic scarring than in the controls (median 93 ml/min per 1.73 m2, range 48-133 vs. 111 ml/min per 1.73 m2, range 89-121, P < 0.05), and the urine albumin excretion was significantly higher (median 20 micrograms/min per 100 ml GFR, range 0.8-170 vs. 9.2 micrograms/min per 100 ml GFR, range 3.3-21, P < 0.05). An inverse correlation was found between urine albumin excretion and GFR. Increased urine albumin excretion was found in 70% of the children with a GFR below 90 ml/min per 1.73 m2 compared with 41% of the children with a GFR above this level. Increased urine albumin excretion (> 20 micrograms/min per 100 ml GFR) was found in 51% of the children with pyelonephritic scarring, while only 14% had increased age-adjusted serum creatinine concentrations. The high incidence of microalbuminuria in children with pyelonephritic scarring indicates long-term follow-up until the ultimate outcome has been better defined.

Interleukin-1 alpha and interleukin-1 receptor antagonist in the urine of children with acute pyelonephritis and relation to renal scarring.

Urinary concentrations of interleukin-1 alpha (IL-1 alpha) and interleukin-1 receptor antagonist (IL-lra) standardized to urinary creatinine concentrations were studied. The median standardized IL-1 alpha creatinine quotient in children with first-time acute pyelonephritis was 3.6 pg/mumol, but was nondetectable in children with recurrent pyelonephritis, children with non-renal febrile conditions and children convalescent after acute pyelonephritis (p < 0.05-0.01). IL-lra levels were also significantly higher in children with acute first-time pyelonephritis (median of 239 pg/mumol) compared to these three groups of children (p < 0.01-0.001). The highest urinary IL-lra levels, however, were found in the healthy controls (median value 1.019; p < 0.001). Both cytokines were higher among children younger than one year compared to older children. The acute IL-1 alpha creatinine quotients were lowest in children with uptake defects on 99mTC-dimercaptosuccinic acid (DMSA) scintigraphy both during the acute infection (reflecting the acute inflammation) (p < 0.001) and 1 year after the acute infection (reflecting permanent kidney scarring) (p < 0.001). In conclusion, persisting high urinary levels of IL-1 alpha were associated with less renal inflammation and scarring.

Functional parameters and 99mtechnetium-dimercaptosuccinic acid scan in acute pyelonephritis.

The diagnostic value of 99mtechnetium-dimercaptosuccinic acid (DMSA) scintigraphy, ultrasonography and renal functional parameters [urine N-acetyl-beta-D-glucosaminidase (NAG)/creatinine and urine albumin/creatinine quotients] in acute pyelonephritis (APN) were studied in 39 children (28 girls, 11 boys, median age 9 months, range 2 weeks to 9.4 years, 28 patients < 1 year, 11 patients > 1 year) with first-time urinary tract infection. Ultrasonography of the urinary tract was performed on admission and together with DMSA scintigraphy (< 10 days from admission). Urine NAG/creatinine and urine albumin/creatinine quotients were measured daily and after 6-8 weeks. Ultrasonography revealed abnormalities in 12 of 39 (31%) patients [11/32 patients (34%) with positive DMSA scintigraphy], while DMSA uptake defects were present in 32 of 39 (82%) patients [21/28 < 1 year (75%), 11/11 > 1 year (100%), P = 0.08]. Urine NAG/creatinine and urine albumin/creatinine quotients were significantly higher in children < 1 year with APN, as well as in non-renal fever controls, than in older children. However, in both age groups the urine NAG/creatinine and urine albumin/creatinine quotients were significantly higher in APN than in non-renal fever. The urine NAG and albumin excretion decreased rapidly after the initiation of antimicrobial therapy and had normalized at 6-8 weeks. The size and grade of the DMSA uptake defect (DMSA score) did not correlate with duration of disease at admission, maximum C-reactive protein or maximum fever. The urine NAG/creatinine quotient in the children < 1 year showed, however, a significant correlation with the DMSA score (r = 0.58, P < 0.05), while no correlation was found in the older children. We conclude that DMSA scintigraphy is a sensitive method to confirm the clinical diagnosis of APN, although a substantial number of infants appear to have normal scans. Early determination of the urine NAG/creatinine and albumin/ creatinine quotients may further improve the diagnostics in the infant.

Urine interleukin-6 and interleukin-8 in children with acute pyelonephritis, in relation to DMSA scintigraphy in the acute phase and at 1-year follow-up.

The relationship between urine interleukin-6 (IL-6) and interleukin-8 (IL-8)/creatinine quotients and 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy, performed within 10 days of acute first-time pyelonephritis and after 1 year, was studied in 41 children. The urine IL-6 and IL-8/creatinine quotients were also related to the urine N-acetyl-beta-D-glucosaminidase (NAG) and albumin/creatinine quotients. Presence of DMSA uptake defects, reflecting local inflammation, in children in the acute phase of pyelonephritis, were associated with elevated urine IL-6/creatinine quotients (median 27 pg/mumol); in children without DMSA changes there was no increase in quotients (median non-detectable) (P < 0.05). Persistent DMSA changes at the 1-year follow-up, probably reflecting renal scarring, were only seen in children with increased urine IL-6/creatinine quotients in the acute phase (P < 0.01). No correlation was found between urine IL-8 and DMSA uptake defects. Vesicoureteral reflux (VUR) at 6-8 weeks did not correlate with the urine cytokine levels in the acute phase. The urine excretion of NAG and albumin, reflecting renal dysfunction, was associated with values of both urine IL-6 and IL-8/creatinine quotients, but not with DMSA defects or VUR. Thus, the initial urine IL-6/creatinine quotients might be used as an indicator of risk for persistent renal damage in acute pyelonephritis.

[Radiologic findings in the kidney of children with severe reflux. Five-year comparative study of conservative and surgical treatment]. / Radiologische Nierenbefunde bei Kindern mit schwerem Reflux. Fünfjahresvergleichsstudie konservativer und chirurgischer Behandlung.

The renal findings revealed by intravenous urography (IVU) in 306 children (73 boys, 233 girls) are reported. The children were seen at eight European centres and enrolled in an international study comparing medical and surgical management of children with urinary tract infection and severe vesico-ureteric reflux who were followed for 5 years. In all, 155 children were randomly allocated to medical and 151 to surgical treatment. The protocol and the investigative techniques were standardized, and randomization, data collection and analysis were performed centrally in Essen, Federal Republic of Germany. At entry 149 (49%) had established renal scarring (79 medical, 70 surgical). Presence of normal kidneys (105), areas of thinned parenchyma (52) and grade of reflux were also evenly distributed. IVU was repeated at 6, 18 and 54 months, and serial urine culture, 99mtechnetium-dimer-captosuccinic acid scans and plasma creatinine estimations were performed. Follow-up was complete in 272 children (89%). In 174 children (57%: 90 medical, 84 surgical) there was renal growth without morphological change. New renal scars developed in 19 children treated medically and 20 treated surgically; 12 (5 medical, 7 surgical) developed in previously normal kidneys. Six followed postoperative obstruction. No significant difference in outcome was found between medical and surgical management in terms of the development of new renal lesions or the progression of established renal scars.

Renal scars and parenchymal thinning in children with vesicoureteral reflux: a 5-year report of the International Reflux Study in Children (European branch).

A total of 321 children less than 11 years old with nonobstructive grade III or IV vesicoureteral reflux and with previous urinary tract infection was randomly allocated to medical or surgical treatment in the European branch of the International Reflux Study in Children. (Randomization was stratified for age, sex, grade of reflux, presence of renal scarring, interval since last urinary tract infection and treating hospital). The results of excretory urography are reported for 233 girls and 73 boys treated according to the random allocation, 89% of whom were followed for 5 years. After 5 years in the medical group (155 children) new renal scars were seen in 19 and new renal parenchymal thinning in 11. The proportions were almost identical among 151 children allocated to surgical treatment with 20 new scars and 15 new thinnings. Progression of established scars was also similar in both groups. However, the new scars developed sooner after surgery than during medical treatment. In 6 surgically treated children postoperative obstruction was followed by the development of new scars. In addition, 12 patients showed new scars approximately 6 months after successful surgery, while in only 2 children scars developed more than 6 months after surgery. In 11 children of the medical group new scars were seen more than 6 months after allocation. More new scars developed in the children with parenchymal thinning at entry (23%) than in those with scarred or normal kidneys at entry (10% each) (p < 0.05). The younger the patients at entry, the higher the frequency of new scars (less than 2 years 19.8%) 2 to 4 years 9.8% and 5 years or more 4.6%, p < 0.05).

Five-year study of medical or surgical treatment in children with severe reflux: radiological renal findings. The International Reflux Study in Children.

The renal findings on intravenous urography (IVU) are reported in 306 children (73 boys, 233 girls) from eight European centres entered into an international study comparing medical and surgical management of children with urinary tract infection and severe vesico-ureteric reflux followed for 5 years. One hundred and fifty-five children were randomly allocated to medical and 151 to surgical treatment. Protocol and investigative techniques were standardised and randomisation, data collection and analysis were performed centrally in Essen, Germany. At entry 149 (49%) has established renal scarring (79 medical, 70 surgical). Children with normal kidneys (105), areas of thinned parenchyma (52) and grade of reflux were also evenly distributed. IVU was repeated at 6, 18 and 54 months and serial urine culture, 99mtechnetium-dimercaptosuccinic acid scans and plasma creatinine estimations were performed. Two hundred and seventy-two children (89%) completed this follow-up. In 174 children (57%), (90 medical, 84 surgical) there was renal growth without morphological change. New renal scars developed in 19 children treated medically and 20 surgically; 12 (5 medical, 7 surgical) developed in previously normal kidneys. Six followed post-operative obstruction. No significant difference in outcome was found between medical or surgical management in terms of the development of new renal lesions or the progression of established renal scars.

Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood--a 27-year follow-up.

In a previous report the long-term prognosis of 30 patients with renal scarring after pyelonephritis in childhood was described. In this study, we have related the extent of renal scarring present in childhood to the conditions in early adulthood. A radiological progression of scarring from childhood to adulthood was seen in one-third of the kidneys. The 7 patients with bilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate and higher plasma vasopressin at follow-up than 13 healthy controls. The 20 patients who had unilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate, higher diastolic blood pressure and higher plasma renin at follow-up than controls; 4 had hypertension. The most important finding was that children with unilateral disease are at risk of serious long-term complications. Filtration fraction at follow-up was higher in patients with extensive renal scarring in childhood compared with those with a normal renal area or small scars in childhood (r = -0.43, P less than 0.05). This may indicate glomerular hyperfiltration by remnant glomeruli. This paper emphasizes t the potential seriousness of childhood urinary tract infections especially when early infantile infections are overlooked. A follow-up of more than 4 decades may be necessary before the ultimate prognosis can be established, especially in patients with unilateral renal disease. It is advised that most patients with post-infectious renal scars are followed as high-risk patients, and that treatment continuity is established between paediatricians, nephrologists and, when required, obstetricians.

99mTechnetium dimercaptosuccinic acid scintigraphy in the diagnosis of acute pyelonephritis in rats.

The use of 99mtechnetium dimercaptosuccinic acid (99mTc-DMSA) scintigraphy for the early diagnosis of pyelonephritis has been evaluated in a study performed on adolescent female Sprague-Dawley rats exposed to an ascending Escherichia coli infection. The rats were studied with DMSA scintigraphy either before and 5 days after the infection or 5 and 28 days after the infection. One group of rats received anti-microbial treatment during days 6-11. After the last DMSA scintigraphy the rats were sacrificed and the kidneys prepared for light microscopy study. Kidney morphology was normal and DMSA uptake was high and homogeneous in all control rats. The majority of the rats exposed to E. coli developed inflammatory changes, on light microscopy which extended to various degrees in the renal parenchyma. Five days after the infection the DMSA uptake was consistently reduced, if the inflammatory lesion on light microscopy involved more than 15% of the renal cortex. Twenty-eight days after infection the inflammatory changes were less extensive than at 5 days. The DMSA uptake had usually improved. At this time, however, areas of decreased DMSA uptake could be detected even if the light microscopy changes involved less than 15% of the parenchyma. Microscopical lesions were less frequent and less extensive in the treated than in the untreated rats. The complete return to normal of previously abnormal DMSA uptake was only observed in treated rats. In a few untreated rats cortical scars had formed by day 28. The scars appeared in areas with decreased DMSA uptake at 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of vesicoureteral reflux and urinary tract infection on renal growth in children with upper urinary tract duplication.

The growth of the renal parenchyma was examined in children with duplicated outflow systems, vesicoureteral reflux (VUR), urinary tract infection (UTI) and no sign of obstruction. Ten patients with reflux occurring only in the caudal system (group A) and 4 patients with reflux both to the caudal and the apical system (group B) were studied shortly after their first UTI (study 1) and then 1.5 to 9 years later (study 2). The frequency of UTI was relatively high during the follow-up period. At urography, renal length and renal area were normal in group A in studies 1 and 2. Parenchymal thickness of the apical pole (APT/L) did not differ from normal values in any of the studies. Parenchymal thickness of the caudal pole (CPT/L) was significantly smaller than normal in both studies. There was also a significant decrease in CPT/L between study 1 and 2. UTI during the first year of life was associated with a greater reduction in CPT/L. The determination of renal length and renal area in children with a duplicated ureter, VUR and UTI, does not identify subjects at risk of developing renal growth retardation while serial determinations of parenchymal thickness appear to be an appropriate method.

Ascending pyelonephritis in young rats retards kidney growth.

Several radiological studies have suggested that pyelonephritis in infancy and childhood may result in kidney growth retardation without renal scarring. In the present study, we induced ascending pyelonephritis in 20-day-old rats with intravesical infusion of E. coli. Four days after infusion, E. coli was cultured from all renal cortex. The rats were either left untreated (PNu) or were treated with trimethoprim-sulfa (PNt). The rats were investigated one month after infection and compared with an age-matched control group (C). Seventy-nine percent of the PNu rats had recovered spontaneously from infection. Body weight was the same in all groups. In PNu rats, kidney weight (KW), kidney area (KA) and glomerular filtration rate (GFR) were significantly decreased. KW, KA and GFR were similar in PNt and C rats. The numbers of filtering nephrons were not reduced by the infection. The total cortical DNA content (index of cell number) was significantly lower in PNu (5.30 +/- 0.32 mg) and PNt (6.62 +/- 0.44 mg) than in C rats (8.48 +/- 0.49 mg). The cortical DNA content was significantly lower in PNu than in PNt rats. The cortical protein/DNA ratio was significantly higher in PNu rats than in C rats. The protein/DNA ratio was similar in PNt and PNu rats. The increase in protein/DNA ratio was interpreted as a sign of cell hypertrophy. The inflammatory process as such did not increase the protein/DNA ratio. The kidneys were also examined for structural lesions. Signs of scarring, inflammation and cell necrosis were almost absent in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Unilateral hydronephrosis with congenital absence of contralateral kidney in children. Report of six cases and review of literature.

The case histories of six children with absence of functioning renal parenchyma on one side and dilatation of the contralateral pelvis are reviewed. The hydronephrosis was obstructive in two cases. In the others no cause could be found. The development of this combination of renal malformations is discussed against an embryologic background.

Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood.

We have evaluated the long-term prognosis in an unselected group of adult patients either uni-nephrectomized in childhood because of hydronephrosis or born with unilateral renal agenesis. Thirty-six patients aged 7-47 years were followed for 7-40 years. In 23 control subjects aged 20-47 years the glomerular filtration rate (GFR) and the p-aminohippuric acid clearance (CPAH) did not change significantly with age. In patients with a single kidney the size of that kidney was larger and GFR and CPAH were higher than single kidney values in control subjects. However, in patients with a single kidney since childhood the GFR and the CPAH declined slowly but significantly during the follow-up period. Significant microalbuminuria occurred in 47% of the patients with a single kidney and was more frequent with a longer follow-up period. No patient had renal insufficiency or a marked increase in arterial blood pressure. We conclude that in patients with a single kidney since childhood the long-term prognosis is good, but the late decrease in GFR and increase in albumin excretion may indicate a moderate risk for premature renal damage.

Renal parenchymal volume in children. Normal values assessed by ultrasonography.

Forty-three children with normal urograms and with kidneys of normal size regarding length, area and parenchymal thickness were examined using a water-delay computerized ultrasonographic equipment. Renal parenchymal volumes were calculated and related to body weight. The correlation coefficient was 0.92. The renal parenchymal volume of the left kidney was significantly larger than that of the right kidney (p less than 0.001). For practical purposes they should, however, be assumed to be of equal size, 2.0 +/- 0.3 cm3/kg body weight.

Comparison between renal parenchymal sonographic volume, renal parenchymal urographic area, glomerular filtration rate and renal plasma flow in children.

A comparison of renal size, expressed as ultrasonographic renal parenchymal volume and urographic renal parenchymal area, and renal function, measured as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), was made in two groups of children: (1) 21 patients with normal urograms and no signs of current disease and (2) 26 children with recurrent urinary tract infections or asymptomatic bacteriuria. Renal parenchymal volume was calculated using a water delay ultrasonographic device (Octoson). Renal parenchymal area was measured urographically. GFR and ERPF were determined from the clearances of inulin and PAH, respectively. In both groups a good correlation was found between both GFR and ERPF and total renal parenchymal volume as well as renal parenchymal area. The determination of renal parenchymal volume could possibly replace the determination of GFR and ERPF in healthy children and in children with urinary tract infections with normal and abnormal urograms.

Partial ureteric obstruction in the pubescent rat. I. Long-term effects on renal function.

A partial obstruction of the left ureter was created in six-week-old rats. The effects on renal function were studied after three, nine and 15 weeks, first in normal hydration, and then after extracellular volume expansion. Moderate hydronephrosis without parenchymal weight reduction developed within three weeks. The hydronephrotic kidney i) excreted during normal hydration less urine and sodium than the intact one, because of increased reabsorption, ii) was capable of reacting fully on volume expansion and iii) had, after volume expansion, a higher renal blood flow and GFR but also a higher reabsorption of water, sodium, potassium and osmoles, resulting in excretions similar to those on the intact side. The differences noted were small (less than 20%) except for sodium excretion. The hydronephrotic kidney seemed to tolerate an increase in ureteral resistance better than the intact one would do. There were no significant differences between the three, nine and 15-week groups, with regard to the effects on the hydronephrotic kidney. Thus, except for a tendency to sodium retention, the effects of partial ureteric obstruction in young rats seem to be relatively harmless and do not increase with time.

Distribution of renal scars and intrarenal reflux in children with a past history of urinary tract infection.

The distribution of renal scars in children with vesicoureteral reflux (VUR) and a past history of urinary tract infection was studied to see whether a correlation existed between renal scarring and intrarenal reflux. In 37 children with one or more scars in one or both kidneys, scarring was significantly more frequent in the polar areas than in the lateral area. In 7 children with intrarenal reflux (IRR), the distribution of IRR was almost identical with that of renal scarring. When children with marked VUR (grade IV-V) were analyzed separately, a uniform distribution of scars was found. It was concluded that fused papillae, which normally are most frequent in the polar area, are a prerequisite for the development of IRR/renal scars.

A comparative study of size and function of the remnant kidney in patients nephrectomized in childhood for Wilms' tumor and hydronephrosis.

To obtain more information about the natural history of compensatory renal hypertrophy beginning in childhood we traced those who were nephrectomized in childhood for Wilm's tumor (W) and hydronephrosis (Hn) between 1950 and 1978 at one department of surgery in Stockholm. All W patients had received treatment that suppresses cellular division. None of the patients were in renal failure or treated with antihypertensive drugs. All the patients in the follow-up study (22 W, 15 Hn) had a normal contralateral kidney at nephrectomy. Five healthy adults served as controls. The kidney was enlarged in both Hn (142%) and W (125%), but significantly larger in Hn than in W. Renal compensatory growth in W was retarded during the first two years after nephrectomy. The glomerular filtration rate (GFR) was 92% of control in Hn and 82% of control in W. The GFR did not seem to decline with a longer follow-up time in any of the groups. PAH clearance was the same in Hn and W. Albumin excretion was significantly higher in Hn than in W, but not significantly higher in W than in controls. The highest albumin excretion rates were found among the Hn patients with long follow-up time. The results suggest that the large increases in size and function that follow childhood nephrectomy can be blunted by antimitotic agents.

Renal involvement in the Laurence-Moon-Biedl syndrome. Functional and radiological studies.

The renal abnormality of the Laurence-Moon-Biedl syndrome (LMBS) was investigated in six patients. The glomerular filtration rate (CIn) and the effective renal plasma flow (CPAH) were evaluated by standard clearance techniques and the single injection method, and the maximal concentration capacity was estimated by the ddAVP test. The kidney surface area and length were related to the body surface area, as well as the lumbar vertebrae L1-L3, and the relationship with the GFR was studied. All six patients showed renal abnormalities: Five had small kidneys with reduced GFR and concentrating ability, and one had hyperaminoaciduria (but normal kidney size). Two patients developed terminal renal failure (one of them was successfully transplanted), illustrating the progressive character of the renal lesion. Three of the patients had had recurrent urinary tract infections, but the radiological changes of the kidneys were of the same character as in the others (symmetrical and irregular parenchymal reduction, and blunting and clubbing of the calyces). Since renal abnormalities, with considerable risk for progression to terminal renal failure, are common in the LMBS, regular urine cultures and blood pressure measurements are probably of great importance.