Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children.

PURPOSE: The American Urological Association convened the Pediatric Vesicoureteral Reflux Guidelines Panel to analyze the literature regarding available methods for treating vesicoureteral reflux diagnosed following a urinary tract infection in children and to make practice policy recommendations based on the treatment outcomes data insofar as the data permit. MATERIALS AND METHODS: The panel searched the MEDLINE data base for all articles from 1965 to 1994 on vesicoureteral reflux and systematically analyzed outcomes data for 7 treatment alternatives: 1) intermittent antibiotic therapy, 2) bladder training, 3) continuous antibiotic prophylaxis, 4) antibiotic prophylaxis and bladder training, 5) antibiotic prophylaxis, anticholinergics and bladder training, 6) open surgical repair and 7) endoscopic repair. Key outcomes identified were probability of reflux resolution, likelihood of developing pyelonephritis and scarring, and possibility of complications of medical and surgical treatment. RESULTS: Available outcomes data on the various treatment alternatives were summarized in tabular form and graphically, and the relative probabilities of possible outcomes were compared for each alternative. Treatment recommendations were based on scientific evidence and expert opinion. The panel concluded that only a few recommendations can be derived purely from scientific evidence of a beneficial effect on health outcomes. CONCLUSIONS: For most children the panel recommended continuous antibiotic prophylaxis as initial treatment. Surgery was recommended for children with persistent reflux and other indications, as specified in the document.

Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children.

The ability of the Schwartz formula (CSCH) to estimate glomerular filtration rate (GFR) accurately was investigated in children with renal disease. 125Iodine-iothalamate clearance (CIO) was used as the reference standard for measuring GFR. Data from 176 CIO studies performed on 133 children (aged between 1 and 18 years) were compared with the simultaneous estimation of GFR by CSCH. The overestimation of GFR by CSCH was inversely proportional to the level of renal function. When CIO was > 90 ml/min per 1.73 m2, CSCH overestimated GFR by only 0.1% +/- 3%, but when CIO was < or = 15 ml/min per 1.73 m2, CSCH overestimated GFR by 164% +/- 42%. When renal function is normal or mildly reduced (GFR > 50 ml/min per 1.73 m2), CSCH overestimated CIO by only 10.3 +/- 3.0%, compared with 90.3 +/- 14.5% when renal function was moderately to severely curtailed (GFR < or = 50 ml/min per 1.73 m2). We conclude that CSCH is valid in predicting GFR only in children with normal renal function and mild insufficiency.

In vitro production of angiotensin II by isolated glomeruli.

The glomerulus has several components of the renin-angiotensin system (RAS). The purpose of this study was to evaluate the ability of glomeruli isolated from adult Wistar-Kyoto rats to produce angiotensin II (ANG II). When isolated glomeruli were incubated in Krebs buffer, the peak concentration of immunoreactive angiotensin (ANG) in the incubation medium, representing simultaneous production and degradation, occurred after 15 min of incubation (3.98 +/- 0.34 pg.mg protein-1.15 min-1, of which 18% was ANG II. When 125I-labeled ANG II was incubated with isolated glomeruli, the half-life of ANG II was 6.06 min. Hence, we estimated ANG II production at 3.77 +/- 0.21 pg.mg protein-1.15 min-1. When angiotensinogen-rich serum was added to the incubation medium, ANG concentration at 15 min increased by 500-fold (1,978 +/- 44 pg.mg protein-1.15 min-1, P < 0.001). ANG concentration in the glomerular incubate responded to perturbations known to alter systemic RAS. Enalaprilat, chymostatin, propranolol, and renin antiserum decreased ANG concentration in glomerular incubate, whereas salt depletion increased this (P < 0.05). We conclude that the rat glomerulus can generate ANG II independent of neural, hormonal, or vascular control.

Glomerular losartan (DuP 753)-sensitive angiotensin II receptor density is increased in young spontaneously hypertensive rats.

There is increasing evidence that an activated intrarenal renin-angiotensin system (RAS) alters renal hemodynamics and fluid balance and that such events may lead to the development of hypertension. To examine the role of the glomerular RAS in the development of hypertension in the spontaneously hypertensive (SHR) rat, we studied angiotensin (ANG) II receptors in isolated glomeruli from young (4- to 5-wk-old) and adult (10- to 12-wk-old) SHR and from age-matched, normotensive Wistar-Kyoto (WKY) rats. Glomerular ANG II receptor density in young SHR is 3-fold higher than in age-matched WKY rats (2033 +/- 154 versus 742 +/- 151 receptors/microns2; p < 0.05) and 1.5-fold higher than in adult SHR and WKY rats (1128 +/- 85 and 1198 +/- 181 receptors/microns2, respectively; p < 0.05). Additional studies demonstrated that the differences in receptor density are not related to disparity in receptor occupancy and that they are also independent of systemic ANG levels. Suppression of RAS by ANG converting enzyme inhibitors resulted in a 3-fold increase in receptor density in young SHR rats and a 4.5-fold increase in young WKY rats; receptor density remained greater in young SHR rats (5915 +/- 318 versus 3358 +/- 234 receptors/microns2, p < 0.05). Furthermore, competitive binding experiments using the nonpeptide ANG II antagonists losartan (AT1) and PD 123319 (AT2) indicate that the greater ANG II receptor density in the young SHR rats represents an increase in the number of a single population of AT1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Etiology of sustained hypertension in children in the southwestern United States.

We reviewed the records of 132 children with persistent hypertension who were evaluated by our pediatric nephrology services between 1987 and 1991. Eighty-nine (67%) of these children were found to have renal or renovascular disease, 30 (23%) had primary hypertension and 13 (10%) had a non-renal cause for their hypertension. Glomerulonephritis (n = 37) and reflux nephropathy (n = 26) were the most frequent renal disorders identified. Renal artery thrombosis was the most common cause of hypertension in the neonatal period (in 6 of 12 neonates, 50%) whereas cystic kidney disease was the most common cause of hypertension in the 1st year of life (in 9 of 30 infants, 30%). The prevalence of primary hypertension increased with age; this diagnosis was made in 16 of 46 (35%) hypertensive patients between 12 and 18 years of age and, more surprisingly, in 8 of 27 (30%) children between 7 and 11 years of age. These data confirm that secondary hypertension is the most common cause of hypertension in children but suggest that primary hypertension is more prevalent than previously recognized in patients between 7 and 18 years of age.

Medical management of mild and moderate vesicoureteral reflux: followup studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group.

Mild and moderate vesicoureteral reflux is expected to resolve spontaneously in most children treated medically; however, maximum benefit or minimum risk of such therapy has not been defined. A prospective 5-year followup study of infants and children younger than 5 years at entry with primary vesicoureteral reflux (grades I to III/V) and radiographically normal kidneys after the first recognized urinary tract infection was initiated in 1984. A total of 113 patients was entered from 5 centers and 61% of the patients were less than 2 years old. Vesicoureteral reflux was unilateral in 65 cases (58%) and bilateral in 48 (42%). Of the 226 renal units reflux was grade IV in 4 (2%), III in 51 (22%), II in 81 (36%) and I in 25 (11%), and 65 (29%) had no vesicoureteral reflux. Data on 59 patients who have completed the protocol were analyzed for this report. Breakthrough urinary tract infection occurred in 20 patients. Of the 84 ureters with vesicoureteral reflux at diagnosis reflux resolved in 67%, and it was of lower grade in 22%, same grade in 8% and higher grade in 2%. Grade I vesicoureteral reflux resolved in 82%, grade II in 80% and grade III in 46% of the ureters. Resolution was better when vesicoureteral reflux was unilateral left (74%) than unilateral right (46%) or bilateral (60%). Renal scarring occurred, on average, in 10% of the kidneys without known vesicoureteral reflux or exposed only to nondilating (grades I and II) reflux and in 28% of those with dilating (grade III) reflux. Thirteen cases had breakthrough urinary tract infection but only after the scar was noted in 5. We conclude that under good medical management during 5 years of followup, even mild and moderate vesicoureteral reflux can be associated with renal injury.

Morphological characteristics of segmental renal scarring in vesicoureteral reflux.

We examined 25 complete and partial nephrectomy specimens from 21 patients with advanced reflux nephropathy, all of which showed severe renal atrophy and loss of parenchyma. All specimens that included nonatrophic or partially atrophic renal tissue contained small medullary scars that involved only portions of the medullary pyramids. These sublobar medullary scars, which appeared linear and were typically discrete, extended from the inner medulla to the cortex. They obliterated collecting ducts, vasa recta and recurrent loops. The cortical portions of the scars contained remnants of nephrons and variable infiltrates of chronic inflammatory cells with lymphoid follicles. Seven of the specimens also contained acute disruptive ductal lesions with histopathological features characteristic of intrarenal reflux. We believe that the linear scars are the result of single duct medullary disruptions, mediated perhaps through obstruction of the several thousand nephrons subtended by each papillary duct and perhaps through localized disruption of the renal microvasculature. These sublobar scars accumulate as scarring progresses to end stage renal atrophy.

Development of renal hemodynamics: glomerular filtration and renal blood flow.

The regulation of RBF and GFR is essential to understanding renal physiology during mammalian development. Without this knowledge, clinical judgment regarding overall renal function in human neonates, especially those considered high risk, is reduced to guesswork. The plethora of reports in which assessment of RBF and GFR were attempted have provided a legacy purporting the neonatal kidney as immature, inadequate and dysfunctional--nothing could be farther from the truth. Our failure to understand kidney function in the neonate does not justify shifting the blame for unwanted disturbances in fluid and electrolyte balance, metabolic acidosis, and azotemia to a small kidney. After a critical stage of renal development has been reached, subsequent changes in RBF and GFR are only quantitatively different from the adult kidney.

Vesicoureteric reflux and renal injury.

Renal injury associated with the intrarenal reflux (IRR) of urine that is either infected, under high pressure, or both, is a major cause of severe hypertension during childhood and adolescence and of chronic renal insufficiency in patients less than 30 years of age. Many, but not all, adolescent and adult patients with reflux nephropathy (RN) give a history of urinary tract infection (UTI) or unexplained fevers in infancy or early childhood, when the kidney is thought to be at greatest risk of injury. Although vesicoureteric reflux (VUR) is observed more commonly in infants than children with UTI, it is rare in uninfected patients at any age and should never be considered a normal finding during human development. Renal scarring may not be obvious in radiographic or radionuclear studies to medical management alone, no definite benefit of one over the other was observed, regardless of the grade of VUR. Moreover, progressive renal injury in scarred kidneys has been noted even after VUR had been corrected, when infection had been prevented, and while hypertension had been controlled satisfactorily. Focal glomerular sclerosis, a lesion found in patients with proteinuria and RN, has been identified not only in scarred kidneys, but also may be seen in contralateral, unscarred kidneys without VUR, which might suggest a humoral factor or, perhaps, a hyperfiltration phenomenon. RN is one of the most frequent causes of end-stage renal disease (ESRD) in children, adolescents, and young adults, which is potentially preventable. However, prevention will depend on early identification of patients at risk--infants and young children after the first UTI and siblings of patients with VUR--aggressive and effective treatment of UTI, minimizing intravesical pressure, and education of patients, parents, and physicians.

Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat.

To examine angiotensin (ANG) concentrations in fluid compartments near known intrarenal ANG receptors, we measured ANG concentrations in glomerular filtrate (GF), star vessel plasma (SVP), and luminal fluid from the early, mid, and late proximal tubule (E, M, and L PT). Samples were collected from euvolemic Munich-Wistar rats by free-flow micropuncture; ANG concentrations were measured by RIA. In one group of rats, concentrations of total immunoreactive ANG (reflecting ANG II and lesser amounts of three fragments) in GF and E, M, and L PT fluid averaged 29-40 nM compared with 32 pM in systemic plasma. In a second group, immunoreactive ANG concentrations in SVP also exceeded systemic levels by a factor of 1,000. In a final group, samples of GF and LPT fluid were purified by HPLC before RIA to measure ANG II and III concentrations specifically: their respective concentrations were 6-8 nM and 14-25 nM. We interpret these results to indicate that substantial amounts of ANG peptides are released into or generated within intrarenal fluid compartments, in which local ANG is likely to effect regulation of renal function independently of systemic ANG.

Postnatal development of renal function during the first year of life.

Several aspects of renal function vary considerably during the 1st year of life and differ markedly from the equivalent values in the adult. Glomerular filtration rate (GFR) increases little, prior to the time an infant reaches a conceptional age of 34 weeks, the point in renal development from which the absolute GFR (ml/min) increases gradually to mature values when linear growth is completed during adolescence. GFR corrected for body size is not comparable with adult normal values until after 12 months of age; therefore, whether GFR is estimated from Scr or measured by timed urine collection, there is no easily recalled range of normal values for infants. One must know the changes in the renal function of normal infants that take place following birth during the 1st year of life. Despite several attempts to do so, renal function during the 1st year of life cannot be assessed from urine flow rate. A urine flow rate of less than 1 ml/kg per hour may be normal and appropriate and may not be harmful either to preterm or full-term infants with normal GFR. Impaired concentrating ability of the neonatal kidney is probably of no clinical significance in all but the most extreme circumstances and is not a major factor in an infant becoming dehydrated, developing hypernatremia or being at greater risk of acute renal injury. Acid-base status in infants must be interpreted appropriately to know when alkali therapy should be introduced to avoid growth failure secondary to true metabolic acidosis. When plasma renin activity is measured in the infant with renal failure of hypertension, one must compare the result with the normal range of values related to postnatal age of normal infants.

Prevention of hereditary nephropathies by antenatal interventions. Ethical considerations.

The identification of renal abnormalities in the human fetus has focused attention on considerations for intervening to correct defects in utero as an alternative to abortion. The fervor which has characterized unproven, though seemingly logical measures attempted unsuccessfully thus far to prevent continued renal injury and pulmonary hypoplasia in the fetus with obstructive uropathy, affords an opportunity to discuss ethical issues which will encumber further experimental approaches for treating the defective human fetus. Such uncharted measures must be scrutinized rigorously not only for valid scientific principles, but also for consideration given to ethical concerns.