The Clinical Significance of Vesicoureteral Reflux

Symposium on Pediatric Nephrology

The Clinical Significance of Vesicoureteral Reflux A. Barry Belman, M.D., M.S.*

The importance of the intact, antireflux ureterovesical mechanism is becoming more and more apparent. There is little question that bacterial pyelonephritis in all ages is almost exclusively the result ofvesicoureteral reflux. The only exception appears to be that which is secondary to urinary obstruction.

Historical Review The ability of the ureterovesicaljunction to prevent the reflux of urine into the upper urinary tract (ureters and renal pelves) has been recognized since the Middle Ages. It remained for Sampson, however, to describe the flap valve mechanism of the submucosal ureter. 65 In 1924 Bumpus performed 1036 cystograms in patients with a number of disease states and discovered an overall incidence of reflux in 8.6 per cent. 6 He noted a causal relationship between reflux and pyelonephritis but also thought that primary renal infections could lead to reflux. Gruber, in a series of experiments published in 1929 and 1930, compared the human ureterovesical junction to those of a variety of laboratory animals and recognized the importance of the well developed trigone for the prevention of reflux. 23 . 24. 25 At about the same time Meredith F. Campbell, the father of pediatric urology, was advocating the simplicity of cystography as a means of defining both reflux and other bladder abnormalities. He stated that cystograms should be done for any known or suspected genitourinary disease and that age was not a contraindication to its performance. He did warn, however, of the risk of sepsis when doing this study in the presence of acute infection.8 Unfortunately, the interest in vesicoureteral reflux waned from that point, and in an issue of Pediatric Clinics devoted exclusively to Pediatric Urology in 1955, the only mention of this entity was in the section on neuromuscular disease. 15 Fortunately, J. A. Hutch had been rekindling interest in vesicoureteral reflux,30 and the results of "Associate Professor of Urology and of Child Health and Development, George Washington University School of Medicine, Washington, D.C. From the Department of Urology, Children's Hospital National Medical Center, and the Department of Urology, George Washington University School of Medicine, Washington, D.C. Pediatric Clinics of North America-Vol. 23, No.4, November 1976

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the first surgical procedures to prevent reflux in children were reported in 1955. 35

The Ureterovesical Junction The antireflux mechanism of the normal ureterovesical junction works primarily on a flap-valve principle which is effective even in death. In life the prevention of reflux appears to be more dynamic. The ureter passes through the bladder muscle at Waldeyer's sheath where it has limited muscular attachments. A submucosal course (tunnel) is then pursued to its termination at the ureteral orifice. Throughout the length of the intravesical ureter (that which extends from the muscular hiatus to the orifice) its musculature is arranged almost entirely in a longitudinal direction. The muscles on the roof of this segment of ureter are quite sparse, contributing to its flexibility. On the floor of the intravesical ureter, however, the longitudinal fibers are abundant. It is these muscles on the floor of the ureter which continue beyond the ureteral orifice to help make up the superficial detrusor. The minimal attachment of the ureter at the muscular hiatus allows for a degree offlexibility. As the bladder fills, its muscular wall rides up the ureter at Waldeyer's sheath effectively lengthening the submucosal tunnel. With voiding the detrusor contracts, pulling the ureteral orifice toward the bladder neck, again effectively lengthening the submucosal ureter. 3!. 32 If the length of the submucosal tunnel contributes significantly to the efficiency of the antireflux mechanism, both these factors may be of great importance in maintaining its integrity. Stephens and Lenaghan, on the other hand, feel that contraction of the longitudinal muscles of the roof of the submucosal ureter effectively closes the ureteral orifice. 66 It has been demonstrated that the antireflux mechanism remains intact even if the ureteral orifice is disconnected from the superficial detrusor. 26 These mechanisms combine to prevent reflux in the normal human. Cystograms performed in 66 premature infants 55 and in 26 neonates less than 48 hours after birth 46 failed to reveal reflux in any. On the other hand, in various laboratory animals reflux has been recognized as a normal phenomenon. 24 Factors Influencing Reflux Because of experimental discrepancies and the more frequently recognized association of reflux in patients with neurogenic disease and obstruction at the bladder neck and urethra, the impression was gained that vesicoureteral reflux was primarily an abnormality secondary to distal obstruction. 67 A period then ensued during which revision of the bladder neck was carried out either as a routine with ureteroneocystotomy or as a separate step.42 At the present time specific obstructions are dealt with individually based on objective evidence of their existence, and at most centers bladder neck revision is no longer carried out as a routine coincident with reimplantation. Of interest is a study by Fisher and Darling 21 revealing that the control of reflux was no better served by bladder neck revision alone than by medical treatment alone. Factors which do appear to influence reflux primarily involve the submucosal distal segment of ureter from the point at which it enters the

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bladder (muscular hiatus) to its termination at the ureteral orifice. 40a The average ratio of the length of this segment of ureter to its diameter has been observed to be 5: 1 in the normal but only 1.4: 1 in a group ofrefluxing children54 (Fig. lA). Therefore, assuming that the point of entrance of the ureter at its muscular hiatus is relatively constant in man, the more lateral the position of the ureteral orifice the shorter the submucosal tunnel and the more prevalent reflux. 2 Lyon et al. 48 classified orifice configuration and position, noting a direct correlation between the severity of reflux and the position of the ureteral orifice in relation to the bladder neck. Orifice configuration correlates with submucosal tunnel length. Thereby inspection of the orifice endoscopically allows the examiner an estimation of the adequacy of the submucosal "valve." Distortion of the ureterovesical junction, such as by a paraureteral diverticulum (Fig. Ie), may also promote reflux. Although initially described in patients with neurogenic disease, paraureteral diverticula also present in otherwise normal urinary tracts 31 and, if situated immediately adjacent to the ureteral muscular hiatus, distort the ureterovesical junction as the bladder fills. Herniation of bladder mucosa through this defect may weaken the support of the intravesical ureter, resulting in reflux. The incidence of reflux is greater in patients with duplication of the collecting system than in the general population. The expected incidence

Bladder wall

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c

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A

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PARAURETERAL DIVERTICULUM

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Figure 1. Factors influencing unreterovesical junction: A, Normal: The ureter pursues an adequate submucosal course. B, Cystitis: The mucosa is edematous and the submucosal ureter becomes rigid interfering with normal antireflux mechanism. C, Paraureteral diverticulum: The ureterovesical junction becomes distorted as the bladder fills shortening or obliterating completely normal submucosal ureteral course. D, "Golf-hole" orifice: There is total absence ofthe submucosal ureter. The orifice is more lateral in trigone than normal. E, Partial absence of submucosal tunnel. The child may outgrow the reflux. F, Neurogenic bladder: Normal strong muscular backing of submucosal ureter is lacking; reflux may result. (Modified from King, L. E., Surian, M. A., Wendel, R. M., et al.: Vesicoureteral reflux: A classification based on cause and the results of treatment. J.A.M.A., 203:169,1968.)

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of complete duplication ofthe collecting system is 1: 500. However, in a review of 73 children with vesicoureteral reflux the incidence was 1:4.5. 3 As the duplicated ureters descend from the kidney to the bladder, they cross. The ureter from the lower renal segment enters the bladder more superolaterally than its mate which drains the upper renal segment (Meyer-Weigert law). The result is a shortened submucosal tunnel in the lower segment ureter. Therefore, when reflux is present in duplication it invariably involves the ureter to this lower segment18 (Fig. 2). One of the great controversies regarding the subject at hand revolved around whether reflux causes infection or vice versa. Urologic dogma of long standing has related urinary infection to urine stasis. The contribution ofvesicoureteral reflux, particularly when severe, to residual urine is evident. An early therapeutic measure based on this principle recommended multiple micturition in an effort to reduce this residual. 64a The apparent contribution of reflux to infection is exemplified in a group of patients with urinary tract infection and vesicoureteral reflux followed after ureteroneocystostomy. Only 14 per cent of those patients with a successful outcome persisted in having infection, whereas infection was noted in 64 per cent of those with continued reflux. 72 The ability of inflammation to cause rigidity of the ureterovesical junction has been recognized since 1924. 6 Submucosal injections of physiologic saline at the ureterovesical junction have been demonstrated to produce transient reflux in laboratory studies. 4

Figure 2. A, Intravenous urogram in girl with complete, bilateral duplication of collecting system. Note blunting oflower calyces. B, Cystogram in same child demonstrating reflux into both lowering collecting systems only.

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The most vocal proponent of the theory that reflux is primarily secondary to urinary tract infection states that reflux will disappear after specific antibacterial therapy in 85 per cent. 61 Although all who deal with the problem acknowledge that reflux secondary to infection is not uncommon, it would not appear that its occurrence is as great as was suggested at that time. The true incidence will remain unknown as long as acute infection is controlled prior to performance of cystography, a practice advocated by most clinicians in the field today. Finally, orifice position and the presence ofvesicoureteral reflux appears, in some instances at least, to be based on a polygenic (multifactorial) inheritance 7 or as a dominant gene with incomplete penetrance. 52 The absolute preponderance offemales in almost every large series (5: 1)14 and its rarity in blacks would tend to corroborate the genetic aspect of this problem. The Diagnosis of Reflux The diagnosis of vesicoureteral reflux is made radiographically. Whether spot films or cineradiographic methods are employed remains a matter of personal preference. 59. 63 It is apparent that dynamic studies with the patient awake are more productive than expression cystography under anesthesia.71 At the same time voiding films in boys, outlining the entire urethra, are imperative to rule out urethral abnormalities, whereas visualization of the female urethra is clinically noncontributory, exposing the patient to unnecessary gonadal radiation. 60 Residual urine, ureterectasis, ureteral tortuosity, linear streaks indenting the renal pelvis or ureter, calyceal abnormalities, and renal atrophy have been reported as intravenous urographic signs which suggest reflux. 51 Additionally, adequate but delayed visualization of a poorly functioning, refluxing renal unit may result when contrast media excreted by the more normal contralateral kidney are refluxed from the bladder into the abnormal collecting system. 1 In such circumstances one might assume a greater degree of function exists for that kidney than is real. Intravenous urography or radioisotope renography with an indwelling catheter in place to prevent reflux may be necessary to assess the true degree of remaining renal function. The best means of identifying vesicoureteral reflux continues to require invasion with a urethral catheter. Spot films taken with the bladder filled in the anterior-posterior and both oblique positions, in addition to a post-void film, should identify those patients with a clinically significant degree of reflux. An alternative method, which is highly attractive in view of the reduced amount of radiation involved, is radionuclide cystography.lO Catheterization is still necessary and image resolution is not comparable to radiographic methods; however, for long-term follow-up of patients on a medical regimen the margin of safety in terms of radiation exposure justifies its use. Incidence Radiographic evaluation of patients presenting with urinary infections reveals reflux in from 35 62 to 50 per cent. 22 Those with reflux tend to be sicker and to present at an earlier age (2 or 3 years) than those in whom this finding is absent. Sixty per cent of those with reflux have

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fever associated with infection, whereas this is true in only 8 per cent without reflux. 22 Unfortunately fever does not appear as often in infants with this problem. Failure to thrive and vomiting are the most common symptoms associated with urinary tract infection in the very young. 58 There is also a high incidence of diarrhe a in infants who have significant urinary pathology.62 With this in mind, urinalysis becomes imperative in the child with the symptoms cited above. Gross pyuria on microscopic examination was present in all the patients reported by Smellie et al. 62 with reflux and urinary tract infection. Nevertheless, urine culture with colony count remains the definitive means of making the diagnosis of infection.

Reflux and Pyelonephritis The relationship between vesicoureteral reflux and bacterial pyelonephritis is becoming increasingly apparent. The effectiveness of the normal flap-valve mechanism at the ureterovesical junction is essentially complete. Radioactive labeled sulfur colloid placed in the bladders of dogs does not migrate into the ureter in the absence of reflux. 11 On the other hand, when reflux was surgically produced in rats, carbon particles placed in the bladder were found to enter the kidney and pursue the course of the intrarenallymphatic system. These particles pass from the collecting system through the renal fornices along the course of the interlobar and arcuate vessels, evoking a wedge-shaped inflammatory response corresponding to the patterns ofthe scarring seen in clinical pyelonephritis. 12 Numerous clinical reviews have demonstrated in both adults and children the correlation between reflux, bacterial infection of the urinary tract, and renal changes recognized as consistent with pyelonephritis. Hodson, in his criteria for the radiographic diagnosis of pyelonephritis, notes that these changes are usually focal, start in the medulla affecting the entire area from the calyx to the cortex, and produce retraction of both these surfaces, i.e., cortical scarring and caliceal blunting. 27 Owing to the focal nature of the disease the capsular retraction is uneven, usually involving the polar calices, and is surrounded by normal renal tissue giving an uneven appearance to the renal outline. If scarring is severe, the kidney size is smaller than anticipated. In his vast radiographic experience, Hodson states that atrophic pyelonephritis is distinctly a disease of childhood and that he has never recognized scarring which was initiated in adult years. Scott and Stansfeld57 supported this relationship between reflux and scarring in their review of the x-rays of 201 children with a history of urinary infections. Eighty-five per cent of the scarred units had reflux. Similar findings have been reported by Filly et al. 19 and Hutch et al. 36 Along the same lines, cystograms performed in adults with radiographic changes consistent with pyelonephritis have revealed an incidence of reflux ranging from 23 9 to 70 per cent.17 Alternatively the overall incidence of reflux in 903 adults evaluated with a variety of urologic complaints was only 5 per cent.17 In another interesting review of adults, Vermillion and Heale 70 found that in 89 per cent of scarred kidneys either reflux persisted at the time of evaluation or the ipsilateral ureteral orifice was noted to be malpositioned endoscopically and predictably might have refluxed in the past, whereas renal scarring was seen in only 4 per cent of

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the control group in which the ureteral orifice was normal. Dwoskin and Perlmutter 14 reported a 10 per cent incidence of renal scarring in the absence of reflux, and Govan et al. 22 found only one scarred kidney of285 in which reflux was not present. It would appear, then, that reflux is directly responsible for the majority of renal scarring and, according to many observers, these changes are initiated in early childhood. 22 What makes the infant kidney so much more susceptible to damage than that of the adult? Intrarenal reflux, a phenomenon not generally seen after 5 years of age, has been indicated by Rolleston et al. 56 Using baby pigs, which apparently have kidneys architecturally similar to the human's, Hodson et al,28 produced scarring corresponding to that which results from intrarenal reflux associated with bacterial infection in children. Hutch37 concluded that scarring limits the growth of childhood kidneys, exaggerating the degree of damage. Sterile Reflux It has been suggested that sterile reflux has the ability to damage kidneys, apparently by hydrostatic pressure. 55a This has not been verified in large groups of patients in whom reflux was followed closely for many years while infection was controlled 40,62 and in laboratory studies. 39 , 53 Scarring has been reported to progress in patients with reflux when an intermittent antibiotic regimen has been followed, treating each infection for 2 or more weeks. 22 , 45 In our own personal experience long-term continuous medication controls the risk of renal infection and scarring as long as bacteriuria is prevented. It is essential that the patient and her family understand the importance of the prophylactic regimen until such time as reflux stops spontaneously or is surgically corrected if the risk of scarring is to be minimized. A word of caution must be advised at this point. When reviewing x-rays and noting the appearance of new scars one must be aware that it takes up to 2 years after an acute infection for new scars to develop.19. 29 This delay in scar maturation may be responsible for some ofthe criticism of antireflux surgery to prevent renal scarring, particularly if the surgical correction was prompted by a febrile illness. Renal Insufficiency We must discuss those patients who present with severe renal insufficiency, reflux, and, often, hypertension. In fact, hypertensive symptoms may be the first signs of illness. In many of these patients, particularly the males, a history of urinary infection cannot be elicited or the degree of pathology is disproportionate to the number of known infections. 47 , 68 Urinary tract evaluation demonstrates a markedly dilated system on cystography with poor visualization pyelographically. The kidneys and renal pelves have a "flower pot" configuration on the cystogram (Fig. 3). Ureteral orifice position is far lateral, and if histologic examination is performed at an early age, renal changes are compatible with the diagnosis of dysplasia. 49 This constellation is suggested as being the result of an embryologic abnormality of the ureteral bud and nephrogenic mass. 16 Extensive studies correlating orifice configuration and duplication of the collecting system have lent support to this theory,50 and a developmental abnormality seems to explain those cases in which a bacterial etiology is not applicable. This finding has been noted to be familial. 43

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Figure 3. Cystogram in male infant who failed to thrive. Note collecting system has "flower-pot" configuration with dilated pelvis and relatively small infundibula and calyces typical of dysgenetic system. The child was azotemic at the time of presentation at 4 months of age.

It has been suggested that dysplastic kidneys are more susceptible to bacterial damage. 5 Bacteria are thought to lodge in the blind ending nephrons or in primitive connective tissue, thus becoming less available for the normal immunologic protective responses to infection. Secondary inflammatory obliteration of underlying tissue then explains the failure to find dysplastic changes histologically in specimens examined in older age groups. 64 The ultimate result is "end-stage kidney disease," although this same clinical study has been called primary interstitial nephritis. 68 Clinical Management

The information presented in the previous pages has been an effort to lay the groundwork for an intelligent approach to the patient with vesicoureteral reflux. The significance of reflux in the face of urinary infection and its association with morbidity and renal damage have been repeatedly stressed in an effort to arrive at a few reasonable conclusions upon which the clinician can hang his hat. H the evidence is correct, it would appear that reflux must be diagnosed in the first few years of life ifrenal scarring is to be prevented. It has been our experience that those patients who have renal scarring presented to us that way. Since the average age of diagnosis of reflux and presentation for urologic assessment is 3 years, the injury must have occurred at some time prior to that unless we are to assume the changes are congenital. It is apparent that not everyone is susceptible to renal scarring even in the presence ofurinary infection and reflux. Even some who have clinical

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episodes of high fever, abdominal pain, vomiting, pyuria, and a positive culture do not later develop radiographic changes of pyelonephritis. Perhaps more than reflux and infection is necessary to produce renal changes. Perhaps pyelotubular backflow during the early years or a focus of dysplasia serving as a nidus for bacterial infection is necessary to eventually produce scarring. Regardless, the conclusion follows that routine urine screening for bacteriuria should be performed periodically during the first 3 years oflife. If that is too impractical, then the minimum acceptable practice is urinalysis and urine culture in the infant or child who has fever which is not otherwise absolutely explainable, has diarrhea or colic, is fretful, or fails to thrive. Since reflux is found in from one third to one half of patients evaluated after urinary tract infection is diagnosed and 35 per cent of those with reflux have renal scarring,14 prudence would suggest that patients with infections documented by culture should at least have radiographic evaluation after their first infection. This concept is reinforced by the knowledge that 80 per cent of patients with one infection will have another;22 thus waiting for the second infection is statistically unsound reasoning. It has been our policy to wait several weeks after the acute infection before undertaking radiographic evaluation. This is an effort to weed out those patients who have transient, clinically insignificant reflux associated with cystitis. In the interim it is advisable to check the urine again with the child off medication to assure the absence of infection prior to the x-rays. If infection recurs, serious consideration should be given to continuation of treatment until the radiographic evaluation is completed. Additionally, one might elect to maintain antibacterial therapy until the x-rays are done in patients who are highly suspicious for reflux, e.g., those who were toxic and febrile at the time of urinary infection. It has always been apparent that reflux occurs much more often in children than adults, a historical factor which probably contributed to the delay in the recognition of its significance. Unless the majority of children with reflux die, something must change which results in its cessation. Hutch 32 suggested there was maturation of the intravesical ureter and reported that from birth to adulthood the length of the submucosal tunnel tripled. Lenaghan and Cussen 44 noted reflux in 80 per cent of32 puppies investigated under 2 months of age. At 6 months only 5 per cent continued to demonstrate this finding. Since all organs greatly enlarge during the same period, perhaps some degree of muscular growth or maturation also is responsible. 65 In our own clinical experience with a somewhat selected group,40 slightly over half the patients followed without surgery eventually outgrew reflux, the vast majority of these before 11 years. Lenaghan et al. 45 reported almost identical findings, stating that 50 per cent of their patients stopped refluxing by age 6 and 68 per cent by age 14. In both studies it is apparent that those ureters which are more severely dilated and those with shortened submucosal tunnels and laterally placed orifices have the least chance of outgrowing reflux. With this in mind endoscopic evaluation is carried out in all patients in whom reflux is found and the length of the submucosal tunnel mea-

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sured (Fig. 4). The ureteral orifice is visualized directly and its configuration noted and classified according to Lyon's de scription. 48 A 4 French ureteral catheter is passed up the ureter and, using the centimeter marks on the catheter as a guide, the amount of mucosa elevated by the catheter is recorded. One cm is usually normal in children, and 0.5 cm normal in infants. Tunnels less than 2 mm in length are thought of as being grossly abnormal. It is extremely unlikely that those ureters with little or no submucosal tunnel length will outgrow reflux, and it is in this group that a surgical procedure is generally recommended at the time of initial diagnosis. It is not within the realm of this article to discuss surgical techniques; the interested reader is referred to a review of the subject by Tanagho.69 It should be noted, however, that the success of reimplantation is determined to some extent by the degree of dilatation of the ureter41 and condition of the bladder. The chances of favorable result approach 95 per cent in the best of circumstances. 13 The purpose of surgery is to protect the kidneys, and although successful reimplantation does not eradicate recurrence of cystitis completely, it does prevent pyelonephritis and further risk of renal damage. 22 For the majority of patients who have some likelihood of outgrowing reflux a conservative course is followed. It is abundantly clear that sterile reflux is not injurious to the kidney and causes no patient morbidity. On this basis it is our policy to maintain those patients in whom reflux is being followed on a twice daily dose of sulfa or nitrofurantoin. The reports of Filly et at}9,20 and Lenaghan et al. 45 confirm my personal prejudice that intermittent therapy leads to progression of scarring, a finding I have not noted in a large group of patients on continuous prophylaxis for up to 6 years. Finally, a word about those patients who present with severe reflux and renal insufficiency usually associated with hypertension (reflux nephropathy). In some of these patients unrecognized or mild urinaI1( infec-

Figure 4. Endoscopic evaluation and measurement of ureteral orifice and length of submucosal ureter using a 4 French ureteral catheter. (From King, L. R, Kazmi, S. 0., Campbell, J. A., and Belman, A. B.: The case for nonsurgical management in vesicoureteral reflux. In Scott, R (ed.): Current Controversies in Urologic Management. Philadelphia, W. B. Saunders Co., 1972, p. 205.)

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tions may have caused more damage than anticipated because ofunderlying dysplasia producing progressive renal, including glomerular, changes. 3s The prognosis in this group of patients is very poor. Control of infection has been the most meaningful contribution in terms of preventing further renal damage, although relative deterioration may be inevitable in the young child who has fixed renal reserves which are rapidly outgrown. Antireflux surgery has not improved the prognosis unless infection cannot be controlled by more conservative means. Ureteral reimplantation did not appear to alter the course of patients reported by Stickler et al.,68 either.

CONCLUSIONS It is difficult to draw up a list of conclusions that are not controversial. There are, however, some inevitable truths which, I believe, can be stated: 1. Vesicoureteral reflux is primarily the result of an anatomic abnormality of the ureterovesical junction. A small percentage of children with urinary tract infection will have transient reflux which has little or no clinical significance. The problem of dealing with this group will be diminished if cystography is postponed for 6 weeks after acute infection, allowing the edema which provokes this type of reflux to resolve. 2. Vesicoureteral reflux is in itself intrinsically not injurious to the kidneys. Studies of patients in whom infection has been controlled have amply demonstrated that the hydrostatic pressure effect of reflux causes no damage and that it is the combination of reflux allowing access of bacteria to the kidneys which provokes morbidity and renal scarring. 3. Bacterial pyelonephritis provokes more damage in younger kidneys, although not all patients are susceptible to renal scarring in spite of repeated episodes of clinical infections. Scarring occurs uncommonly in older age groups. 4. Over half to two thirds of all patients have an excellent chance of outgrowing reflux. Based on the anatomic configuration of the ureteral orifice, orifice position, and length of the submucosal tunnel, a prediction can be made and a clinical course planned. Long-term follow-up while on prophylactic antimicrobials with periodic radiographic evaluation can safely be carried out until such time as reflux is no longer demonstrated or surgical correction performed. 5. A small group of patients present with severe renal damage, impressive ureterectasis, and, if bilateral, renal insufficiency. It is likely that these are primarily congenital changes which have occurred on the basis of an abnormal ureteral bud. A portion of these patients have secondary bacterial scarring. 6. Surgical repair of the ure terove sic al junction is a technically satisfactory procedure which should probably not be postponed when it is apparent the child will not outgrow reflux. Protection of the kidneys is virtually assured after successful surgery in spite ofthe fact that recurrent cystitis may well continue to be a problem. Progression of renal scarring in the postoperative period is likely due to scar maturation from infection that occurred prior to surgical repair.

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REFERENCES 1. Amar, A. D.: Vesicoureteral reflux causing improved visualization on the delayed excretory urogram. Radiology, 101 :1, 1971. 2. Ambrose, S. S., and Nicholson, W. P., III: Vesicoureteralreflux secondary to anomalies of the ureterovesical junction: Management and results. J. Urol., 87:695, 1962. 3. Ambrose, S. S., and Nicholson, W. P., III: The causes ofvesicoureteralrefluxin children. J. Urol., 87:688, 1962. 4. Auer, J., and Seager, L. D.: Experimentallocalbladder edemacausing urine reflux into the ureter and kidney. J. Exp. Med., 66:741, 1937. 5. Bialestock, D.: Renal malformations and pyelonephritis: The role ofvesicoureteral reflux. Aust. N. Z. J. Surg., 33:114, 1963. 6. Bumpus, H. C., Jr.: Urinary reflux. J. Urol., 12:341, 1924. 7. Burger, R. H., and Smith, C.: Hereditary and familial vesicoureteral reflux. J. Urol., 106:845, 1971. 8. Campbell, M. F.: Cystography in infants and in childhood. Am. J. Dis. Child., 39:386, 1930. 9. Cervadio, C., and Shachner, A.: Observations on vesicoureteral reflux and chronic pyelonephritis in adults. J. Urol., 103:722, 1970. 10. Conway, J. J., King, L. R., Belman, A. B., et al.: Detection ofvesicoureteral reflux with radionuclide cystography. A comparison study with roentgenographic cystography. Am. J. Roentgenol. Rad. Ther. Nuc. Med., 115:720,1972. 11. Corriere, J. N., Jr., Kuhl, D. E., and Murphy, J. J.: The use of 99mTc labeled sulfur colloid to study particle dynamics in the urinary tract. Invest. Urol., 4:570, 1967. 12. Corriere, J. N., and Murphy, J. J.: Vesicoureteral reflux and the intrarenallymphatic system in the rat. Invest. Urol., 4:556, 1967. 13. Devine, P. C., Davis, C. S., Devine, C. D., Jr., et al.: VesicoureteraI reflux in children. Urology, 3 :315, 1974. 14. Dwoskin, J. Y., and Perlmutter, A. D.: Vesicoureteral reflux in children: A computerized review. J. Urol., 109:888,1973. 15. Emmett, J. L., Simon, H. B., and Mills, S. D.: Neuromuscular disease of the urinary tract in infants and children. Pediat. Clin. North Am., 2:803, 1955. 16. Ericsson, N. 0., and Ivemark, B. 1.: Renal dysplasia and pyelonephritis in infants and children. Part 1. Arch. Path., 66:255, 1958. 17. Estes, R. C., and Brooks, R. T.: Vesicoureteral reflux in adults. J. Urol., 103:603, 1970. 18. Fehrenbaker, L. G., Kelalis, P. P., and Stickler, G. B.: Vesicoureteral reflux and ureteral duplication in children. J. Urol., 107:862, 1972. 19. Filly, R. A., Friedland, G. W., Govan, D. E., et al.: Urinary tract infections in children. Part II, roentgenologic aspects. West. J. Med., 121 :374, 1974. 20. Filly, R., Friedland, G. W., Govan, D. E., et al.: Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology, 113:145, 1974. 21. Fisher, J. H., and Darling, D. B.: The course of vesicoureteral reflux associated with urinary tract infection in children. J. Pediat. Surg., 2:221, 1967. 22. Govan, D. E., Fair, W. R., Friedland, G. W., et al.: Management of children with urinary tract infections. Urology, 6:273, 1975. 23. Gruber, C. M.: The ureterovesical valve. J. Urol., 22:275, 1929. 24. Gruber, C. M.: A comparative study of the intravesical ureters. J. Urol., 21 :567, 1929. 25. Gruber, C. M.: The function of the ureterovesical valve and the experimental production of hydroureters without obstruction. J. Urol., 23:161,1930. 26. Hannan, Q. H. A., and Stephens, F. D.: The influence oftrigonectomy on vesicoureteraI reflux in dogs. Invest. Urol., 10:469, 1973. 27. Hodson, C. J.: The radiological contribution toward the diagnosis of chronic pyelonephritis. Radiology, 88:857, 1967. 28. Hodson, J., Maling, T. M. J., McManamon, P. J., et al.: Reflux nephropathy. Kidney Int., 8:S-50, 1975. 29. Hodson, C. J., and Wilson, S.: Natural history of pyelonephritis scarring. Brit. Med. J., 2:191, 1965. 30. Hutch, J. A.: Vesicoureteral reflux in the paraplegic: Cause and correction. J. Urol., 68:457, 1952. 31. Hutch, J. A.: Saccule formation at the ureterovesical junction in smooth walled bladders. J. Urol., 86:390, 1961. 32. Hutch, J. A.: The theory of maturation of the intravesical ureter. J. Urol., 86:534, 1961. 33. Hutch, J. A., and Amar, A. D.: Diagnostic procedures in urinary tract infection. In Vesicoureteral Reflux and Pyelonephritis. New York, Appleton-Century-Crofts, 1972. 34. Hutch, J. A., Ayers, R. D., and Loquvam, G. S.: The bladder musculature with special reference to the ureterovesical junction. J. Urol., 85:531,1961. 35. Hutch, J. A., Bunge, R. G., and Flocks, R. H.: Vesicoureteral reflux in children. J. Urol., 74:607, 1955.

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Department of Urology Children's Hospital National Medical Center 2125 Thirteenth Street, N.W. Washington, D.C. 20009