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Vesicoureteral reflux
Vesicoureteral
Reflux*
Role in Pyelonephritis* JOHN
A.
HUTCH,
EARL
R.
MILLER
San Francisco,
D
ESPITE intensive
clinical and laboratory research, many features of pyelonephritis remain unexplained. Two types of pyelonephritis are recognized: obstructive and nonobstructive. Obstructive uropathies are well understood. When obstruction is present anywhere in the urinary tract (renal pelvis, ureter, bladder neck or below), infection is difficult to eradicate unless the obstruction is removed. Above the obstruction the urinary tract loses its best defense against infection, namely, the ability to empty completely. As a result, the urinary tract infection becomes chronic. However, many infections occur in unobstructed urinary tracts. The etiology of non-obstructive pyelonephritis remains obscure. The demonstration by Kass and others [ 71 of the great frequency with which bladder urine is infected, particularly in women, supplies part of the answer, but finding significant numbers of bacteria in a culture of bladder urine does not necessarily mean that the patient has pyelonephritis. These bacteria could be resident in the bladder, they could originate in the upper part of the urinary tract en route to the outside, or they could be in transit upward to the kidneys. We propose to explain non-obstructive pyelonephritis by showing that vesicoureteral reflux is the mechanism by which infection of the bladder spreads to the kidneys. We will support this thesis by reviewing the existing information on vesicoureteral reflux, by describing twentytwo of our own patients (all of them adults with non-obstructive pyelonephritis and vesicoureteral reflux), and by explaining how reflux can perpetuate a urinary tract infection even in the absence of obstruction.
and FRANK
HINMAN,
JR.
California EXISTING
INFORMATION
ON
VESICOURETERAL
REFLUX
The Intermittency of Refux. During the last decade much has been learned about the fickle nature of reflux. Most pathologic changes demonstrated on roentgenograms are reproducible, and it has been difficult for us to realize that this is not always true when reflux is involved. For example, a patient whose cystogram reveals right reflux today may not show reflux when re-examined tomorrow. A week from now this same patient may show left reflux and a month from now, bilateral reflux. This point was brought out statistically by McGovern, Marshall and Paquin [2]. They studied forty-three patients in whom reflux was present in sixty-four ureters. In a second examination six months later, fourteen ureters which had shown reflux on the first examination failed to show reflux on the second study, and eleven ureters which had not shown reflux on the first examination did so on the second. Not only does reflux vary from one examination to another, but also it varies from film to film in the same cystographic study. For example, in a four-film cystogram there may be right reflux on the initial film, no reflux on the second film, bilateral reflux on the film taken during voiding and left reflux on the film taken after voiding. This variation from film to film is known to all who work with reflux and was first described in the literature by Stewart [3] and Bunge [4] in 1953. In the early cystograms the bladder was filled with contrast medium, and a single x-ray film was made. As time passed it was learned that if more films were made the percentage of demonstrable reflux would increase.
* From the Division of Urology and Department of Radiology, University of California School of Medicine, San Francisco, California. This study was supported in part by U. S. Public Health Service Grant CS-9440 (E. R. M.) and by a grant from the American Urological Association, Inc. (F. H.). Manuscript received May 8, 1962. 338
AMERICAN
JOURNAL
OF
MEDICINE
Vesicoureteral
Refiux --Hutch et al. TAELE
INCIDENCE OF REFLUX
-
-
1Yo. ol F 1Reflux
Source and Date
Cases
(%)
Campbell [9],1951. St. Martin et al. [ 701,1956.
722 74
12 13.5
Kjellberg et al. [77], 1958.
290
34
Forsythe, Wallace [ 72],1958
51
39
McGovern et al. [2], 1960. Palken, Kennelly [73], 1960
152 53
Gross, Sanderson [ 14],1961 Hutch et al. [75], 1962.. -
35 37.5
83
47
190
48
34,
MARCH
1963
I
IN CHILDREN WITH PYELONEPHRITIS
T Type of Cystogram
Type of Patients
Immediate and after voiding Immediate, voiding and after voiding Voiding cystourethrography (multiple films during voiding)
Children with pyuria and enuresis Children with bladder neck obstruction Children with urinary tract infection obstruction or without neurologic lesion Children with recurring urinary tract infection Symptomatic children Girls with recurring urinary tract infection Children with recurring urinary tract infection Children and adults with urinary tract infection
i
Gradually a delayed film, a film after voiding and a cystourethrogram during voiding were added to the study. Now that cinefluoroscopy is available and a complete voiding cycle can be watched, some of the variable results of the earlier cystograms can be explained. As the bladder fills and empties during the filming of a three minute movie during voiding, the changes characteristic of reflux often may be present for only fifteen or twenty seconds. Even with which is the most sensitive cinefluoroscopy, method available for the detection of reflux, a negative study does not rule out the possibility that reflux may have been present in the past or that it will not be present and demonstrable in the future [5]. Refrux May Be Present in Patients Whose IntraIt has been venous Pyelograms Are Normal. recognized for years that reflux may be present in patients with badly distorted bladders and dilated upper urinary tracts such as occur in severe obstructive uropathies, neurogenic bladders and urinary tract tuberculosis. More recently it has become apparent that reflux may be present even when the intravenous pyelogram is normal [S]. Minor, non-specific pyelographic changes, which in the past had not been thought to be significant, are proving to be associated with reflux in a high percentage of cases [7,8]. These pyelographic changes include minimal dilatation of the lower third of the ureter and minor pyelonephritic changes in undilated kidneys. It is becoming evident that VOL.
339
Voiding cystogram (multiple films during voiding) Multiple films, some during voiding Voiding cystourethrography and cinefluoroscopy Cinefluoroscopy Cinefluoroscopy
reflux is not limited to patients with grossly distorted upper urinary tracts but that it may coexist with such common urinary tract infections as recurring pyelonephritis and chronic pyelonephritis even when the ureter and renal pelvis are still essentially normal. Increasing Incidence of Rejlux in Children with Urinary Tract Infections. The striking increase in the incidence of demonstrable reflux in children with urinary tract infections during the last six years is illustrated in Table I and is worth careful study. These figures of rising incidence reflect the increasing interest in the subject as well as improved technics for the demonstration of reflux, i.e., the cystourethrogram obtained during voiding and cinefluoroscopy. Just what is the significance of this rising incidence of demonstrable reflux? In our own series at the University of California, we reviewed the first 190 movies made during voiding and found that reflux was present in ninety-two cases, for an incidence of 48 per cent. However, our cases were selected, and many of the patients were known to have reflux before being sent to us. On the other hand, we have many cases in which reflux had been demonstrated on previous cystograms but not during cinefluoroscopy. Although these patients are included in our statistics as not having reflux, we know that on certain occasions they do have reflux. In Gross and Sanderson’s [74] cases, cinefluoroscopy was performed as the initial diagnostic study. Even under these conditions, they found thirty-nine
Vesicoureteral Reflux-Hutch et ai.
340
TABLE SUMMARY
OF TWENTY-TWO
PATIENTS
PYELONEPHRITIS
Cast No.
WITH WITH
II
NON-OBSTRUCTIVE VESICOURETERAL
-
(RECURRENT
OR CHRONIC)
REFLUX
Azo temi;
Blood Pressure (mm. Hg)
Yes
220/100
Bilateral chronic pyelo nephritis; non-functioning left kidney
Bilateral reflux
Asymptomatic; hypertension found on routine physical examination (Fig. 1)
Pyelogram
Cystogran
Clinical Course
1
I
-. II
28,F
No
146/100
Bilateral chronic pyelo. nephritis
Bilateral reflux
Recurring pyelonephritis as a child and again since marriage; hypertension began during second pregnancy and has persisted -_-
III.
32,F
No
Normal
Chronic pyelonephritk on right side; atrophic pyelonephritis on lefi side
Reflux or I left side
Intermittent attacks of chills, fever and pyuria beginning at age 22; averages about one attack a year (Fig. 2)
I”
33,Iv
Yes
210/160
Bilateral chronic pyelo. nephritis
Bilateral reflux
Asymptomatic; age 19
”
58,F
No
Normal
Atrophic pyelonephritir on right side; normal left kidney
Reflux onI right side
Asymptomatic; studied because of lower back pain and unexplained pyuria (Fig. 3)
“I
27,F
No
Normal
Pyelonephritis on right side; normal left kidney
Reflux on right side
Onset of recurring attacks of cystitis pyelonephritis on the right side
VII
40,F
No
150/100
Atrophic pyelonephritir on left side; normal right kidney
Reflux onI left side
Recurring pyelonephritis logic symptoms since occasional cystitis
27,F
No
Normal
Normal
Reflux on right side
Severe recurring pyelonephritis as a child; since the birth of her second child has recurring attacks of cystitis and pyelonephritis on the right side
34,F
No
Normal
Bilateral chronic pyelonephritis
Bilateral reflux
Recurring attacks of pyelonephritis as a child; three bouts of pyelonephritis with first pregnancy at age 26; now asymptomatic but has constant pyuria in spite of therapy (Fig. 4)
30,F
Yes
Normal
Bilateral chronic pyelonephritis
Bilateral reflux
Onset of pyelonephritis at age 18; at age 27 atrophic pyelonephritic left kidney removed; now recurring pyelonephritis on right side and constantly infected urine
23,F
No
Normal
Chronic pyelonephritis on left side; normal right kidney
Reflux on left side
Recurring attacks of pyelonephritis on left side since birth of first child at age 16
28,F
No
Normal
Chronic pyelonephritis on left side; normal right kidney.
Reflux on left side
16,F
No
Normal
__-
___-_
--
albuminuria
-VIII
--
-_
-IX
--
---
x
-XI
-xn
-
,
_-
__
Bilateral chronic pyelonephritis -
and
as a child; no uroage 12 except for __-___
_-
__
-XIII
at
______-
-_
--
first noted
Recurring attacks of acute pyelonephritis on left side began 1 year ago at age 27; six attacks during this 12 mo. period (Fig. 5) -_
Recurring attacks of fever, chills and abdominal pain all her life; left kidney removed surgically at age 11 (Fig. 6)
Bilateral reflux -
-
AMERlCAN
JOURNAL
OF
MEDICINE
Vesicoureteral
Reflux-Hutch
TABLE
SUMMARY or
TWENTY-TWO
PYELONEPHRITIS
Case No.
PATIENTS
Age
Blood Pressure (mm. Hg)
CYYJ .!\ZOt1
ernla
Sex
II
WITH WITH
Pyelogram
341
et al.
(Continued) NON-OBSTRUCTIVE VESICOURETERAL
(RECURRENT
OR
CHRONIC)
REFLUX
-
Clinical
( Iystogram
Course
i= XIV
70,F
xv
34-F
XVI
16,F
No
II
Normal
Chronic pyelonephritis on right side
on 1ieflux right side
Asymptomatic
Yes
Normal
Bilateral chronic nephritis
pyelo-
1Bilateral reflux
Pveloneohritis first occurred when oatient was in’ college; left nephrectomy a*nd hilateral ureterovesical plasty in 1954; asymptomatic hut urine is constantly infected
No
1 Normal
Bilateral chronic nephritis
pyelo-
1Bilateral
__
hut has persistent
pyuria
_.
XVII
38,F
No
No
16,F
No
(
Normal
Bilateral chronic nephritis
Reflux on right side
Normal
Normal
Reflux on right side
Pyuria, backache and fever as a child until age 8; reflux found accidentally on a cystogram done for another cause --.___-
Reflux on left side
Recurring bilateral pyelonephritis and intermittent infections since age 20; severe attacks at ages 20, 27, 29, 46; reflux pain on right side -~-
No
Normal
Normal
30,F
No
Normal
Normal
pyelo-
46,F
Yt!S
Normal
Bilateral chronic nephritis
___Reflux on right side
pyelo-
Bilateral reflux
!_
cases of reflux in eighty-three patients examined (an incidence of 47 per cent). Assuming that by using the most sensitive technics reflux can be demonstrated in nearly half of the children with recurring urinary tract infections, the true incidence of reflux in this group of patients must be even higher than our highest figures indicate. For example, if reflux were demonstrated in fifty of a hundred children with recurring urinary tract infections, and the fifty in whom reflux was not demonstrated on the first examination were restudied, undoubtedly reflux would appear on the second examination in some of the latter subjects. Also MARCH
Pyelonephritis developed on left side during and after her sixth pregnancy at age 38
Reflux on left side
49,F
34,
severe chiefly
Chronic pyelonephritis on left side; right kidney normal
I
VOL.
Recurring attacks of pyelonephritis, and frequent since age 6; symptoms chills, fever and bilateral hack pain
Normal
_____33,F
reflux
1963
Recurring bilateral pyelonephritis at age 19; 1 to 2 attacks a year _____.
No urologic symptoms till age 27; infected; no symptoms suggestive nephritis; urinary frequency and pressure over bladder _~
beginning
urine not of pyelofeeling of
-I
25 year history of recurring bilateral back pain and chills and fever; chronically infected urine
-(
pointing to the conclusion that the true incidence of reflux is higher than our highest figures indicate is the fact that reflux is more common when the urinary tract is infected than when it is not infected. For example, Thompson [16], using cinefluoroscopy, found fourteen patients with reflux during attacks of acute urinary tract infection; when the patients were re-examined after the infection was cured reflux had disappeared. Others have had similar experiences [9,11,17]. This implies that if these children were studied for reflux during attacks of chills and fever, reflux would be more prevalent than by our present technic in which the child is studied
Vesicoureteral Reflux -Hutch et al.
FIG. 1. Case I. An eighteen year old girl who had been in good health except for occasional headaches was found to have hypertension (blood pressure 220/100 mm. Hg) on a routine physical examination. The urine was infected with Escherichia coli. Intravenous pyelograms failed to show excretion on the left. Differential function tests showed 3 per cent phenolsulfonphthalein excretion in thirty minutes on the left, 15 per cent on the right, and retrograde pyelograms showed atrophy of the left kidney. Cinefluorography showed bilateral reflux without ureteral dilatation and complete emptying of the bladder. pyelogram showing bilateral chronic A, retrograde pyelonephritis. B, single frame from the movie taken during voiding (cinefluoroscopy) showing bilateral reflux into undilated ureters. C, illustrative drawing of B.
at a time when he is clinically well. From this accumulating knowledge about reflux in children it can be concluded that reflux is demonstrable in half of the children with recurring urinary tract infections and undoubtedly is
present in even a larger percentage of these children. It is conceivable that reflux is present intermittently in nearly all of these children. Demonstration of RefEux in Adults with ,Vonobstructiue Pyelone$hritis. Now let us turn our attention to the available information about reflux in adults. In our own experience with cinefluoroscopy at the University of California [78-201 we have demonstrated reflux in many adults with various kinds of urinary tract infection. Of special interest is a group of twenty-two patients with acute recurring or chronic pyelonephritis, with normal-sized ureters and renal pelves (as judged by intravenous pyelography), in whom we have demonstrated reflux by cystography and/or cinefluoroscopy. These cases are summarized in Table II. Recently, Hodson and Edwards [8] reported twenty cases of reflux pyelonephritis in which the intravenous pyelograms revealed the x-ray appearance of nonobstructive pyelonephritis, and the cystograms revealed reflux. Eight of these patients were adults. They also investigated ten patients under treatment for chronic non-obstructive pyelonephritis (unilateral or bilateral) and were able to demonstrate reflux into the involved kidney (or kidneys) in nine of the ten patients. Williams [27] studied sixteen adults with nonobstructive pyelonephritis and found reflux in three. Recently, Milliez et al. [22] investigated ninety-five patients with hypertension and found reflux in nine. They noted that the greatest incidence of reflux occurred in hypertensive patients with previous attacks of pyelonephritis, recent enuresis or renal pain associated with a full bladder and relieved by voiding. Noix [23] also stresses the importance of checking hypertensive patients for reflux. In adults as well as in children a normal cystoscopic examination and normal pyelogram do not rule out the possibility of reflux. Therefore, a urologic study which is complete by present standards misses the reflux which is perpetuating the pyuria or bacteriuria. Even if a cystogram is obtained and reflux is not present, we cannot be certain that intermittent reflux is not the cause of the urinary tract infection. For example, we recently studied a thirty year old woman with recurring urinary tract infections. Urologic studies performed three years ago and one year ago both revealed a normal urinary tract. On the third examination a four-film cystogram was performed which revealed reflux into the lower third of the undilated right ureter AMERICAN
JOURNAL
OF
MEDICINE
Vesicoure teral Reflux-Hutch
et al.
FIG. 2. Case m. A thirty-two year old woman who began to have intermittent attacks of chills, fever and pyuria at age twenty-two. She had no associated history of attacks of cystitis and no definite kidney pain. The blood urea nitrogen was 16.7 mg. per cent and blood pressure lZO/SS mm. Hg. Urine culture showed Escherichia coli. Urinalysis revealed intermittent pyuria. Intravenous and retrograde pyelograms showed an atrophic chronic pyelonephritic kidney on the left and a chronic pyelonephritic kidney on the right. The cystogram revealed reflux into the left undilated ureter and kidney. A, intravenous pyelogram showing poor visualization bilaterally. B, retrograde pyelogram showing an atrophic chronic pyelonephritic (hypoplastic) kidney on the left and a chronic pyelonephritic kidney on the right. A cystogram reveals left reflux into an undilated ureter. Reflux could not be demonstrated on the right. The failure to demonstrate reflux does not rule out the existence of reflux at some time in the past.
on one film only. Cinefluoroscopy failed to demonstrate this reflux. This is not one isolated example, as it has been observed many times in both children and adults. It leaves one with the belief that reflux may be present even when our most sensitive tests fail to reveal it. The observation noted in the discussion of reflux in children, that reflux may be present when the urinary tract is infected and disappear after the infection is cured, is just as valid in adults, leading to the disquieting conclusion that reflux is often missed by studying these patients when they are clinically well. Many children and some adults cannot void during the cystogram, yet in some patients reflux occurs only during voiding. Undoubtedly this fact causes us to miss many cases of reflux even when we look for it. Residual Urine May Represent Refrux Rather Than Vesical Neck Obstruction. Urologists who believe that bladder neck obstruction is the cause of reflux and recurring urinary tract infections have pointed to the demonstration of residual urine as the irrefutable proof of their belief. However, cinefluoroscopy shows that the great majority of these patients empty their bladders completely but that the bladder is refilled after VOL.
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1963
voiding by the return of refluxed urine from the ureters. The concept of bladder neck obstruction implies that a high intravesical pressure is present and that this causes the disease of the upper urinary tract. Efforts to demonstrate this abnormally high intravesical pressure in children with recurring urinary tract infections without obvious obstruction have failed [24-261. Our own demonstration of low pressure reflux* in many children who do not demonstrate reflux during voiding (high pressure) further weakens the position of those who insist that reflux is a product of high intravesical pressure secondary to bladder neck obstruction
[271*
Rejlux Is Being Demonstrated in Diseases in which Its Presence Had Not Been Suspected. As studies of vesicoureteral reflux are being extended, new correlations with a number of urinary tract diseases are evolving. For example, several workers [8,1 I, 78,79,21,28] have been impressed with the high incidence of reflux in atrophic or * Low pressure reflux is a term used to describe reflux which occurs early in the voiding cycle, as the bladder is just beginning to fill and when the intravesical pressure is at its lowest point.
Vesicoureteral
Reflux-Hutch
FIG. 3. Case v. A fifty-eight year old woman who had excretory urograms ten years earlier as part of a routine investigation of lumbosacral back pain and pyuria. The urograms showed atrophy of the right kidney. Cystoscopy
in 1961 showed a gaping right ureteral orifice. Retrograde pyelograms confirmed the findings of the previous excretory urograms. Cinefluorography showed reflux up an undiiated right ureter. After a right nephroureterectomy, her course was uneventful. Pathologic examination of the removed kidney showed marked atrophic pyelonephritis. A, retrograde pyelogram showing an atrophic chronic pyelonephritic (hypoplastic) kidney on the right with a normal appearing left kidney which has undergone compensatory hypertrophy. B, cine-
fluoroscopy reveals reflux illustrative drawing of B.
into
the
right
ureter.
C,
et al.
FIG. 4. Case IX. A thirty-four year old woman who had some symptoms of urinary tract disease in childhood, but no further trouble until eight years ago when she had three bouts of pyelonephritis during her first pregnancy. Intravenous pyelograms taken at that time were normal. Her urine has been infected for the last year in spite of therapy. Recent intravenous pyelograms, when compared with previous ones, showed a decrease in size of both kidneys, especially on the right, without ureteral dilatation. Cystoscopic examination showed large, gaping orifices. Cinefluoroscopy showed bilateral reflux into undilated ureters. A, intravenous pyelogram showing bilateral chronic pyelonephritis. B, cinefluoroscopy reveals bilateral reflux. C, illustrative drawing of B.
hypoplastic kidneys in both children and adults. We [19] have suggested that these small kidneys may be the result of overwhelming infection secondary to reflux which occurs in early neonatal life. As a result, the kidney ceases to grow and remains the size it was when the AMERICAN
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Vesicoureteral
Reflux--- Hutch et al.
5A
5B
FIG. 5. Case XII. A twenty-eight year old woman who had no history of urinary tract disease until one year ago. At that time she had a severe attack of pyelonephritis on the left side. During the last year she had six recurrences. The bladder emptied normally, but her urine was infected intermittently. Intravenous pyelograms were normal except for some slight pyelonephritic changes in the upper calyx on the left side. The cystogram revealed left reflux. A, intravenous pyelogram showing early pyelonephritic changes on the left side. B, cystogram reveals reflux into an undilated left kidney and ureter. This reflux was present only on the immediate film of the cystogram.
infection occurred. If this occurs bilaterally and is not fatal, it produces the clinical picture of renal rickets. Hodson and Edwards [8] examined eight patients with renal rickets and found reflux in six. We have suggested also that reflux may be an etiologic factor in obstruction of the ureteropelvic junction [19]. According to Hanley [29], about 15 per cent of normal renal pelves are of the “closed” type. They can effect the transport of urine under normal conditions, but under conditions of overhydration they cannot rid themselves of the increased amount of urine that is formed and, as a result, begin to dilate. Given this type of renal pelvis, together with reflux early in life, it is suggested that refluxed urine could produce the overload needed to dilate the renal pelvis permanently in the manner that we now accept as typical of primary obstruction of the ureteropelvicjunction. Reflux has been demonstrated in a number of patients who complain of renal pain when their bladder is full and whose pain is relieved by voiding. A few patients who complain of renal pain during voiding have been shown to have reflux. VOL. 34,
MARCH
1963
The Concept of Maturation of the Intravesical Ci-eter. It is agreed generally that the ease with which a ureterovesical valve may be made incompetent varies inversely with the length of the intravesical segment of the ureter, or conversely, the shorter the intravesical segment, the greater is the tendency for reflux to develop in it. Hutch [30] has found that at birth the intravesical segment measures about 5 mm.; in adults it averages about 13 mm. He also found that the adult length of the intravesical ureter is achieved at about twelve years of age. This explains why reflux is more common in children than in adults and presumably accounts for the clinical observation that many children who have recurring urinary tract infections seem to recover spontaneously about the time of puberty. Association Between Urinary Tract Infections in Children and Pyelonephritis in Adults. As more information becomes available, it is increasingly evident that there is a direct relationship between urinary tract infections in children and adults. Jawetz [31] has proposed that the individual attack of acute pyelonephritis should be viewed as an episode in a prolonged disease
Vesicoureteral
Reflux-Hutch
et al.
GA
6B
FIG. 6. Case XIII. A sixteen year old girl had recurring attacks of upper abdominal pain, chills, fever and fatigue all her life. At age seven intravenous pyelograms showed bilateral pyelonephritis, and at age eleven a cystogram showed bilateral reflux. Her left kidney was removed surgically and proved to be a small pyelonephritic kidney weighing only 41 gm. Her infections persisted and a recent study by cinefluoroscopy revealed reflux into the remaining kidney and reflux into the left ureteral stump. These roentgenograms were made prior to the left nephrectomy. A, intravenous pyelogram showing bilateral chronic pyelonephritis. The left kidney has undergone atrophy. B, cystogram reveals reflux into the left ureter and kidney and into the right lower ureter.
process rather than as an isolated event. Hutch [5l has presented a hypothesis in which he attempts to explain the natural history of urinary tract infection on the basis of the status of the ureterovesical junction and the ease with which bacteria may reach the bladder in each age group in each sex. The common urinary tract infections in children occur predominantly in girls and usually take the form of pyelonephritis rather than cystitis. The high incidence of infection is explained by the short urethra and poor hygiene of the child: the sex predilection for girls (9:l) by the short female urethra. The high incidence of pyelonephritis is the result of the combination of frequent bladder infections and the short immature intravesical ureter of
the child, leading to reflux of infected bladder urine to the kidney. Many patients who have repeated attacks of pyelonephritis during early childhood seem to recover by themselves in late childhood or early adolescence. This presumably is because hygiene improves and the intravesical ureter elongates with maturity. During adolescence practically no new cases of pyelonephritis develop. These few teen-age patients whom we do see are holdovers from a severe form of the childhood disease. As the girl begins to lead a sexual life, cystitis again becomes common. Usually the adult ureterovesical junction can confine the infection to the bladder, but in some patients who have a short intravesical ureter or a damaged ureterovesical junction AMERICAN
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Vesicoureteral Reflux--Hutch et al. from childhood, reflux occurs, producing intermittent attacks of acute pyelonephritis or chronic pyelonephritis. In late adult life pyelonephritis becomes predominantly a disease of males because of the urinary obstruction caused by the enlarging prostate. This is due to structural damage to the ureterovesical junction as the bladder muscle strains to void. Reflux and pyelonephritis result. This accounts for the autopsy finding that pyelonephritis is as common in men as in women. Surgical Correction of Reflux. It is beyond the scope of this paper to discuss the technical aspects of the surgical correction of reflux. However, experience with the surgical correction of reflux has strengthened the hypothesis which considers vesicoureteral reflux to be a causative factor in upper urinary tract infection. Technics have been developed by which reflux can be corrected successfully in a high percentage of patients without damage to the upper urinary tract [32-381. In patients with reflux and recurring urinary tract infection, surgical correction of the reflux usually stops the recurring attacks of chills, fever and kidney pain, and the urine becomes sterile [28,36,38-G]. These results seem to warrant the conclusion that correction of the reflux is a specific treatment. Non-clinical Research on Vesicoureteral Rejlux. Almost all the investigative work on vesicoureteral reflux has been carried out in human subjects, thus obviating the doubt that always exists when the results of animal experiments are applied to human disease. Excellent non-clinical studies of reflux have been carried out in experimental animals and cadavers. Much has been learned about the anatomy of the ureterovesical junction and how it functions as a valve [44-471. Studies in different species reveal a high incidence of reflux in most laboratory animals [48-571. Studies of the comparative anatomy of the trigone and intravesical ureter show that the ease with which reflux occurs in these animals varies inversely with the length of the intravesical ureter and the development of the trigone [48,49]. Reflux can be produced experimentally by cutting the bladder muscle behind the intravesical ureter [&I, enlarging the ureteral orifice [48], cutting Waldeyer’s sheath [46], injecting fluid around the intravesical ureter [SO] and putting foreign bodies in the bladder [57]. Recently, Vivaldi and co-workers [52] injected bacteria (Proteus vulgaris) into the bladders of anesthetized white rats through a VOL.
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1963
suprapubic incision. Fifteen of the twenty-five rats sacrificed two to thirty days later were found to have acute pyelonephritis. To prove that the bacteria were reaching the kidney through the ureter, the left ureter in a group of thirty-four rats was ligated surgically. When the bacteria were injected into the bladders in this group of rats, the left kidney was protected from bacterial invasion in all cases. Sommer [53] added an additional experiment by exposing the bladder and both ureters surgically in anesthetized white rats. He then filled the bladder with indigo carmine and observed the ureters for fifteen minutes. In seventeen of twenty rats so treated, reflux of the blue dye into the ureters occurred. Sommer concluded that the rat was not a good experimental animal for the study of urinary tract infections. How Refux May Perpetuate Urinary Tract Infection. A normal unobstructed bladder rids itself of bacteria by two mechanisms shown experimentally by Cox and Hinman [54]. One, the mechanical emptying of the bladder, rids it of the major portion of the bacteria but does not reduce the bacterial population to zero. The microorganisms remaining in the small amount of urine which wets the lining of the bladder even after complete voiding are eradicated by the intrinsic defense mechanisms of the vesical mucosa . When obstruction is present at the bladder neck or in the urethra, the bladder loses its ability to empty itself completely. If bacteria are introduced into the bladder under these conditions, the remaining volume of infected urine will be too great for the intrinsic defense mechanism of the bladder to eradicate the bacteria and infection will be established. Infection may perpetuate itself in an unobstructed urinary tract if reffux is occurring. Even though the bladder empties completely, it will be partially refilled by the infected, refluxed urine returning from the ureter. This likewise will overwhelm the intrinsic defense mechanisms of the bladder. Although bladder neck obstruction and vesicoureteral reflux are different pathologic processes, each perpetuates urinary tract infection in the same basic manner, namely, by making it difficult for the urinary tract to rid itself of infected urine. Vesicoureteral reflux is additionally dangerous because it supplies the route of access for the bacteria to reach the kidneys.
Vesicoureteral
Reflux -Hutch
COMMENTS
The wide application of the quantitative culture of voided urine has provided a useful tool in the study of the epidemiology of urinary tract infections. The method distinguishes contamination from active infection of the urinary tract, and through its use Kass and others [I] have shown that significant infection of bladder urine is fairly common in asymptomatic women. By assumption, the term bacteriuria has become almost synonymous with pyelonephritis but this obviously is not true. We wish to emphasize that a positive culture of bladder urine means only that the bladder urine is infected. It does not tell us whether the infection is limited to the bladder or involves the kidney as well; nor does it tell us whether the infection reaches the bladder from an external source through the urethra or from the kidney through the ureter. Many children with recurring and chronic pyelonephritis have been studied for reflux. With the most advanced equipment (cinefluoroscopy), reflux can be demonstrated in nearly half of these children. Relatively few adults with pyelonephritis have been studied in this way, but early results indicate that many of them may have reflux. We have included a review of twenty-two of our own patients with non-obstructive pyelonephritis in each of whom reflux has been demonstrated. We have shown how an infection can be perpetuated in an unobstructed urinary tract if vesicoureteral reflux is present. The significance of these interrelated observations is that if reflux is the cause of non-obstructive pyelonephritis, surgical correction of the reflux may prevent further progression of the disease. Our efforts in the immediate future should be directed toward two objectives: (1) to demonstrate the frequency of reflux in adults with non-obstructive pyelonephritis, and (2) to determine whether or not pyelonephritis, in a patient in whom reflux has been demonstrated, can be prevented by surgical correction of the reflux. SUMMARY
Vesicoureteral reflux is being demonstrated increasingly, not only in children who have intermittent bouts of acute pyelonephritis, but also in adults with chronic non-obstructive pyelonephritis. We present twenty-two of our own patients, all adults with recurring or chronic non-obstructive pyelonephritis, in each of whom reflux has been demonstrated.
et al.
Reflux may be intermittent, hence, a negative cystogram does not rule it out. Normal intravenous pyelograms frequently are found in patients with ureteral reflux. Residual urine may represent return of refluxed urine to the bladder rather than vesical neck obstruction. Reflux may be the cause of atrophic pyelonephritis; it may be a factor in obstruction of the ureteropelvic junction and may explain abdominal pain after voiding. The ease with which reflux occurs in the human ureterovesical valve changes with the sex and age of the patient and closely parallels the natural history of pyelonephritis. Animal experiments demonstrate the valvular mechanisms involved in the prevention of reflux. Reflux perpetuates infection by overloading the intrinsic bladder defense mechanism immediately after evacuation of the bladder, by the return of the infected urine to the bladder. Surgical correction of reflux stops the clinical attacks of pyelonephritis and sterilizes the urine. Since asymptomatic infection of the bladder urine has been shown to be more common than previously believed, and since reflux is being demonstrated with increasing frequency, the detection and treatment of reflux may lead to a better understanding of the pathogenesis and treatment of chronic nonobstructive pyelonephritis. REFERENCES
1. QUINN, E. L. and KASS, E. H. Biology of Pyelonephritis. Boston, 1960. Little, Brown & Co. 2. MCGOVERN, J. H., MARSHALL, V. F. and PAQUIN, A. J.. JR. Vesicoureteral reguraitation in children J. Ural., 83: 122, 1960. - 3. STEWART, C. M. Delayed cystograms. J. Ural., 70: 588, 1953. 4. BUNGE, R. G. Delayed cystograms in children. J. Ural., 70: 729, 1953. 5. HUTCH, J. A. Role of the ureterovesical junction in the pathogenesis of pyelonephritis. J. Ural., 88: 354, 1962. 6. Panel discussion on vesicoureteral reflux in children. J. Ural., 85: 119, 1961. 7. MARSHALL, F. C. Excretory urographic changes in children which suggest occurrence of reflux. J. Ural., 87: 681, 1962. 8. HODSON, C. J. and EDWARDS, D. Chronic pyelonephritis and vesicoureteral reflux. Clin. Rndiol., 11: 219, 1960. 9. CAMPBELL, M. Clinical Pediatric Urology. Philadelphia, 1951. W. B. Saunders Co. 10. ST. MARTIN, E. C., CAMPBELL, J. H. and PASQUIER, C. M. Cystography in children. J. Ural., 75: 151, 1956. AMERICAN
JOURNAL
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MEDICINE
Vesicoureteral
Reflux-Hutch
11. KJELLBERG, S. R., ERICSSON,N. D. and RUDHE, U. The Lower Urinary Tract in Childhood. Chicago, 1957. Year Book Publishers, Inc. 12. FORSYTHE,W. J. and WALLACE, I. R. Investigation and significance of persistent and recurring urinary tract infections in children. Brit. J. Ural., 30: 297, 1958. 13. PALKEN, M. and KENNELLY, J., JR. Recurrent urinary tract infections in girls. J. l/rol., 83: 745, 1960. 14. GROSS, K. E. and SANDERSON,S. S. Cineurethrography and voiding cinecystography with special attention to vesicoureteral reflux. Radiology, 77: 573, 1961. 15. HUTCH, J. A., HINMAN, F., JR. and MILLER, E. R. Unpublished data. 16. THOMPSON,I. Personal communication. 17. HANLEY, H. G. Transient stasis and reflux in the lower ureter. &it. J. Ural.. 34: 283, 1962. 18. HINMAN, F., JR. and HUTCH, J. A. Atrophic pyelonephritis from ureteral reflux without obstructive signs. .J. lirol., 87: 230, 1962. 19. HUTCH, J. A., HINMAN, F.. JR. and MILLER, E. R. Reflux as a cause of hydronephrosis and chronic pyelonephritis. J. Ural., 88: 169, 1962. 20. HUTCH. .I. A., HINMAN, F., JR. and MILLER, E. R. Unpublished data. 21. WILLIAMS, D. I. Megacystis and megaureter in children. Bull. New York Acad. Med., 35: 317, 1959. 22. MILLIEZ, P., LAGRUE, G., SAMARCO, P., NOIX, M. and BINET, J. L. Functional signs which cause suspicion of ascending pyelonephritis. Rro. Med. Moyen Orient, 17: 71, 1960. 23. NOIX, M. Cysto-urethral motricity in the course of micturition, its radiocinematography study. Arta urol. belg., 28: 532, 1960. 24. MACKELLER, A. and STEPHENS, F. D. Vesical diverticula in children. Australian @ New Zealand J. Surg., 30: 20, 1960. 25. STEPHENS,F. D. and LENAGHAN,D. The anatomical basis and dynamics of vesicoureteral reflux. J. Ural., 87: 669, 1962. 26. GARRETT, R. A., RHAMY, R. K. and CARR, J. R. Non-obstructive vesicoureteral regurgitation. J. IJrol., 87: 350, 1962. 27. HINMAN, F., JR., MILLER, E. R., HUTCH, J. A., GAINEY, M. D., Cox, C. E. and GOODFRIEND, R. B. Low pressure reflux. J. Ural., in press. 28. JOHNSTON,J. H. Vesico-ureteral reflux: its anatomical mechanism, causation, effects and treatment in the child. Ann. Roy. Coil. Surgeons England, 30: 324, 1962. 29. HANLEY, H. G. The pelviureteric junction: a cinepyelography study. Brit. J. lirol., 31: 377, 1959. 30. HUTCH, J. A. Theory of maturation of the intravesical ureter. J. IJrol., 86: 534, 1961. 31. JAWETZ, E. Urinary tract infections. Disense-aMonth, November 1954. 32. HUTCH, J. A. Vesicoureteral reflux in paraplegics: cause and correction. J. Ural., 68: 457, 1952. 33. HUTCH, J. A., BUNGE, R. G. and FLOCKS, R. H. Vesicoureteral reflux in children. J. Ural., 74: 607, 1955. 34. BISCHOFF,P. F. and BUSCH, H. G. Origin, clinical experiences and treatment of urinary obstructions VOL.
34,
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1963
35.
36.
37.
38.
39.
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41.
42. 43.
44.
45. 46.
47.
48. 49.
50.
51.
52.
53.
54.
et al.
349
of the lower ureter in childhood. J. Ural., 85: 739, 1961. POLITANO,V. A. and LEADBETTER,W. F. Operative technique for correction of vesicoureteral reflux. J. Ural., 79: 932, 1958. PAQIJIN, A. J., JR. Ureterovesical anastomosis: description and evaluation of technique. J. Ural., 82: 573, 1959. LICH, R., JR., HOWERTON, L. W. and DAVIS, L. A. Recurrent urosepsis in children. J. Ural., 86: 554, 1961. WILLIAMS,D. I., SCOTT, J. and TURNER-WARWICK, R. T. Reflux and recurrent infection. Brit. J. Ural., 23: 435, 1961. HUTCH, J. A. Ureteric advancement operation: anatomy, technique and early results. J. Ural., in press. VINSON, C. E., BUNTS, R. C. and HUTCH, J. A. Statistical study of the ureterovesical plastic operation. J. Ural., 78: 611, 1957. LEADBETTER,G. M., JR. and LEADBETTER,W. R. Ureteral reimplantation and bladder neck reconstruction: four and one half years’ experience. J. A. M. A., 175: 349, 1961. PALMER,J. G., JR. and ROONEY,D. R. Vesicoureteral reflux in children. J. M. A. Georgia, 40: 393, 1961. AMBROSE, S. S. and NICOLSON,W. P., III. Vesicoureteral reflux secondary to anomalies of the ureterovesical junction: management and results. J. Ural., 87: 695, 1962. SAMPSON, J. A. Ascending renal infection with special reference to the reflux of urine from bladder into the ureters. Bull. Johns Hopkins Hosp., 14: 334, 1903. SATANI, Y. Histologic study of the ureter. J. Ural., 3: 247, 1919. HUTCH, J. A., AYRES, R. D. and LOQUVAM,G. S. The bladder musculature with special reference to the ureterovesical junction. J. Ural., 85: 531, 1961. UHLENHUTH,E., HUNTER, DE W. T. and LOECHEL, W. Problems in the Anatomy of the Pelvis. Philadelphia, 1955. J. B. Lippincott Co. GRUBER, C. M. Ureterovesical valve. .J. Ural., 22: 275, 1929. GRUBER, C. M. A comparative study of the intravesical ureters in man and in experimental animals. J. Ural., 21: 567, 1929. AUER, J. and SEAGER, L. D. Experimental local edema causing urine reflux into ureter and kidney. J. Expcr. Med., 66: 741, 1937. GRAVES, R. C. and DAVIDOFF, L. M. Study on the ureter and bladder with special reference to regurgitation of vesical contents. J. TJrol., 12: 93, 1924. VIVALDI, E., COTRAN, R., ZANGWILL, D. P. and KASS, E. H. Ascending infection as a mechanism in pathogenesis of experimental non-obstructive pyelonephritis. Prod. Sot. Exper. Biol. @ Med., 102: 242,1959. SOMMER, S. L. Experimental pyelonephritis in the rat with observations of ureteral reflux. J. Ural.! 86: 375, 1961. COX, C. E. and HINMAN, F., JR. Experiments with induced bacteriuria, vesical emptying and bacterial growth on the mechanism of bladder defense to infection. J. Ural., 86: 739, 1961.
Reflux*
Role in Pyelonephritis* JOHN
A.
HUTCH,
EARL
R.
MILLER
San Francisco,
D
ESPITE intensive
clinical and laboratory research, many features of pyelonephritis remain unexplained. Two types of pyelonephritis are recognized: obstructive and nonobstructive. Obstructive uropathies are well understood. When obstruction is present anywhere in the urinary tract (renal pelvis, ureter, bladder neck or below), infection is difficult to eradicate unless the obstruction is removed. Above the obstruction the urinary tract loses its best defense against infection, namely, the ability to empty completely. As a result, the urinary tract infection becomes chronic. However, many infections occur in unobstructed urinary tracts. The etiology of non-obstructive pyelonephritis remains obscure. The demonstration by Kass and others [ 71 of the great frequency with which bladder urine is infected, particularly in women, supplies part of the answer, but finding significant numbers of bacteria in a culture of bladder urine does not necessarily mean that the patient has pyelonephritis. These bacteria could be resident in the bladder, they could originate in the upper part of the urinary tract en route to the outside, or they could be in transit upward to the kidneys. We propose to explain non-obstructive pyelonephritis by showing that vesicoureteral reflux is the mechanism by which infection of the bladder spreads to the kidneys. We will support this thesis by reviewing the existing information on vesicoureteral reflux, by describing twentytwo of our own patients (all of them adults with non-obstructive pyelonephritis and vesicoureteral reflux), and by explaining how reflux can perpetuate a urinary tract infection even in the absence of obstruction.
and FRANK
HINMAN,
JR.
California EXISTING
INFORMATION
ON
VESICOURETERAL
REFLUX
The Intermittency of Refux. During the last decade much has been learned about the fickle nature of reflux. Most pathologic changes demonstrated on roentgenograms are reproducible, and it has been difficult for us to realize that this is not always true when reflux is involved. For example, a patient whose cystogram reveals right reflux today may not show reflux when re-examined tomorrow. A week from now this same patient may show left reflux and a month from now, bilateral reflux. This point was brought out statistically by McGovern, Marshall and Paquin [2]. They studied forty-three patients in whom reflux was present in sixty-four ureters. In a second examination six months later, fourteen ureters which had shown reflux on the first examination failed to show reflux on the second study, and eleven ureters which had not shown reflux on the first examination did so on the second. Not only does reflux vary from one examination to another, but also it varies from film to film in the same cystographic study. For example, in a four-film cystogram there may be right reflux on the initial film, no reflux on the second film, bilateral reflux on the film taken during voiding and left reflux on the film taken after voiding. This variation from film to film is known to all who work with reflux and was first described in the literature by Stewart [3] and Bunge [4] in 1953. In the early cystograms the bladder was filled with contrast medium, and a single x-ray film was made. As time passed it was learned that if more films were made the percentage of demonstrable reflux would increase.
* From the Division of Urology and Department of Radiology, University of California School of Medicine, San Francisco, California. This study was supported in part by U. S. Public Health Service Grant CS-9440 (E. R. M.) and by a grant from the American Urological Association, Inc. (F. H.). Manuscript received May 8, 1962. 338
AMERICAN
JOURNAL
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Vesicoureteral
Refiux --Hutch et al. TAELE
INCIDENCE OF REFLUX
-
-
1Yo. ol F 1Reflux
Source and Date
Cases
(%)
Campbell [9],1951. St. Martin et al. [ 701,1956.
722 74
12 13.5
Kjellberg et al. [77], 1958.
290
34
Forsythe, Wallace [ 72],1958
51
39
McGovern et al. [2], 1960. Palken, Kennelly [73], 1960
152 53
Gross, Sanderson [ 14],1961 Hutch et al. [75], 1962.. -
35 37.5
83
47
190
48
34,
MARCH
1963
I
IN CHILDREN WITH PYELONEPHRITIS
T Type of Cystogram
Type of Patients
Immediate and after voiding Immediate, voiding and after voiding Voiding cystourethrography (multiple films during voiding)
Children with pyuria and enuresis Children with bladder neck obstruction Children with urinary tract infection obstruction or without neurologic lesion Children with recurring urinary tract infection Symptomatic children Girls with recurring urinary tract infection Children with recurring urinary tract infection Children and adults with urinary tract infection
i
Gradually a delayed film, a film after voiding and a cystourethrogram during voiding were added to the study. Now that cinefluoroscopy is available and a complete voiding cycle can be watched, some of the variable results of the earlier cystograms can be explained. As the bladder fills and empties during the filming of a three minute movie during voiding, the changes characteristic of reflux often may be present for only fifteen or twenty seconds. Even with which is the most sensitive cinefluoroscopy, method available for the detection of reflux, a negative study does not rule out the possibility that reflux may have been present in the past or that it will not be present and demonstrable in the future [5]. Refrux May Be Present in Patients Whose IntraIt has been venous Pyelograms Are Normal. recognized for years that reflux may be present in patients with badly distorted bladders and dilated upper urinary tracts such as occur in severe obstructive uropathies, neurogenic bladders and urinary tract tuberculosis. More recently it has become apparent that reflux may be present even when the intravenous pyelogram is normal [S]. Minor, non-specific pyelographic changes, which in the past had not been thought to be significant, are proving to be associated with reflux in a high percentage of cases [7,8]. These pyelographic changes include minimal dilatation of the lower third of the ureter and minor pyelonephritic changes in undilated kidneys. It is becoming evident that VOL.
339
Voiding cystogram (multiple films during voiding) Multiple films, some during voiding Voiding cystourethrography and cinefluoroscopy Cinefluoroscopy Cinefluoroscopy
reflux is not limited to patients with grossly distorted upper urinary tracts but that it may coexist with such common urinary tract infections as recurring pyelonephritis and chronic pyelonephritis even when the ureter and renal pelvis are still essentially normal. Increasing Incidence of Rejlux in Children with Urinary Tract Infections. The striking increase in the incidence of demonstrable reflux in children with urinary tract infections during the last six years is illustrated in Table I and is worth careful study. These figures of rising incidence reflect the increasing interest in the subject as well as improved technics for the demonstration of reflux, i.e., the cystourethrogram obtained during voiding and cinefluoroscopy. Just what is the significance of this rising incidence of demonstrable reflux? In our own series at the University of California, we reviewed the first 190 movies made during voiding and found that reflux was present in ninety-two cases, for an incidence of 48 per cent. However, our cases were selected, and many of the patients were known to have reflux before being sent to us. On the other hand, we have many cases in which reflux had been demonstrated on previous cystograms but not during cinefluoroscopy. Although these patients are included in our statistics as not having reflux, we know that on certain occasions they do have reflux. In Gross and Sanderson’s [74] cases, cinefluoroscopy was performed as the initial diagnostic study. Even under these conditions, they found thirty-nine
Vesicoureteral Reflux-Hutch et ai.
340
TABLE SUMMARY
OF TWENTY-TWO
PATIENTS
PYELONEPHRITIS
Cast No.
WITH WITH
II
NON-OBSTRUCTIVE VESICOURETERAL
-
(RECURRENT
OR CHRONIC)
REFLUX
Azo temi;
Blood Pressure (mm. Hg)
Yes
220/100
Bilateral chronic pyelo nephritis; non-functioning left kidney
Bilateral reflux
Asymptomatic; hypertension found on routine physical examination (Fig. 1)
Pyelogram
Cystogran
Clinical Course
1
I
-. II
28,F
No
146/100
Bilateral chronic pyelo. nephritis
Bilateral reflux
Recurring pyelonephritis as a child and again since marriage; hypertension began during second pregnancy and has persisted -_-
III.
32,F
No
Normal
Chronic pyelonephritk on right side; atrophic pyelonephritis on lefi side
Reflux or I left side
Intermittent attacks of chills, fever and pyuria beginning at age 22; averages about one attack a year (Fig. 2)
I”
33,Iv
Yes
210/160
Bilateral chronic pyelo. nephritis
Bilateral reflux
Asymptomatic; age 19
”
58,F
No
Normal
Atrophic pyelonephritir on right side; normal left kidney
Reflux onI right side
Asymptomatic; studied because of lower back pain and unexplained pyuria (Fig. 3)
“I
27,F
No
Normal
Pyelonephritis on right side; normal left kidney
Reflux on right side
Onset of recurring attacks of cystitis pyelonephritis on the right side
VII
40,F
No
150/100
Atrophic pyelonephritir on left side; normal right kidney
Reflux onI left side
Recurring pyelonephritis logic symptoms since occasional cystitis
27,F
No
Normal
Normal
Reflux on right side
Severe recurring pyelonephritis as a child; since the birth of her second child has recurring attacks of cystitis and pyelonephritis on the right side
34,F
No
Normal
Bilateral chronic pyelonephritis
Bilateral reflux
Recurring attacks of pyelonephritis as a child; three bouts of pyelonephritis with first pregnancy at age 26; now asymptomatic but has constant pyuria in spite of therapy (Fig. 4)
30,F
Yes
Normal
Bilateral chronic pyelonephritis
Bilateral reflux
Onset of pyelonephritis at age 18; at age 27 atrophic pyelonephritic left kidney removed; now recurring pyelonephritis on right side and constantly infected urine
23,F
No
Normal
Chronic pyelonephritis on left side; normal right kidney
Reflux on left side
Recurring attacks of pyelonephritis on left side since birth of first child at age 16
28,F
No
Normal
Chronic pyelonephritis on left side; normal right kidney.
Reflux on left side
16,F
No
Normal
__-
___-_
--
albuminuria
-VIII
--
-_
-IX
--
---
x
-XI
-xn
-
,
_-
__
Bilateral chronic pyelonephritis -
and
as a child; no uroage 12 except for __-___
_-
__
-XIII
at
______-
-_
--
first noted
Recurring attacks of acute pyelonephritis on left side began 1 year ago at age 27; six attacks during this 12 mo. period (Fig. 5) -_
Recurring attacks of fever, chills and abdominal pain all her life; left kidney removed surgically at age 11 (Fig. 6)
Bilateral reflux -
-
AMERlCAN
JOURNAL
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Vesicoureteral
Reflux-Hutch
TABLE
SUMMARY or
TWENTY-TWO
PYELONEPHRITIS
Case No.
PATIENTS
Age
Blood Pressure (mm. Hg)
CYYJ .!\ZOt1
ernla
Sex
II
WITH WITH
Pyelogram
341
et al.
(Continued) NON-OBSTRUCTIVE VESICOURETERAL
(RECURRENT
OR
CHRONIC)
REFLUX
-
Clinical
( Iystogram
Course
i= XIV
70,F
xv
34-F
XVI
16,F
No
II
Normal
Chronic pyelonephritis on right side
on 1ieflux right side
Asymptomatic
Yes
Normal
Bilateral chronic nephritis
pyelo-
1Bilateral reflux
Pveloneohritis first occurred when oatient was in’ college; left nephrectomy a*nd hilateral ureterovesical plasty in 1954; asymptomatic hut urine is constantly infected
No
1 Normal
Bilateral chronic nephritis
pyelo-
1Bilateral
__
hut has persistent
pyuria
_.
XVII
38,F
No
No
16,F
No
(
Normal
Bilateral chronic nephritis
Reflux on right side
Normal
Normal
Reflux on right side
Pyuria, backache and fever as a child until age 8; reflux found accidentally on a cystogram done for another cause --.___-
Reflux on left side
Recurring bilateral pyelonephritis and intermittent infections since age 20; severe attacks at ages 20, 27, 29, 46; reflux pain on right side -~-
No
Normal
Normal
30,F
No
Normal
Normal
pyelo-
46,F
Yt!S
Normal
Bilateral chronic nephritis
___Reflux on right side
pyelo-
Bilateral reflux
!_
cases of reflux in eighty-three patients examined (an incidence of 47 per cent). Assuming that by using the most sensitive technics reflux can be demonstrated in nearly half of the children with recurring urinary tract infections, the true incidence of reflux in this group of patients must be even higher than our highest figures indicate. For example, if reflux were demonstrated in fifty of a hundred children with recurring urinary tract infections, and the fifty in whom reflux was not demonstrated on the first examination were restudied, undoubtedly reflux would appear on the second examination in some of the latter subjects. Also MARCH
Pyelonephritis developed on left side during and after her sixth pregnancy at age 38
Reflux on left side
49,F
34,
severe chiefly
Chronic pyelonephritis on left side; right kidney normal
I
VOL.
Recurring attacks of pyelonephritis, and frequent since age 6; symptoms chills, fever and bilateral hack pain
Normal
_____33,F
reflux
1963
Recurring bilateral pyelonephritis at age 19; 1 to 2 attacks a year _____.
No urologic symptoms till age 27; infected; no symptoms suggestive nephritis; urinary frequency and pressure over bladder _~
beginning
urine not of pyelofeeling of
-I
25 year history of recurring bilateral back pain and chills and fever; chronically infected urine
-(
pointing to the conclusion that the true incidence of reflux is higher than our highest figures indicate is the fact that reflux is more common when the urinary tract is infected than when it is not infected. For example, Thompson [16], using cinefluoroscopy, found fourteen patients with reflux during attacks of acute urinary tract infection; when the patients were re-examined after the infection was cured reflux had disappeared. Others have had similar experiences [9,11,17]. This implies that if these children were studied for reflux during attacks of chills and fever, reflux would be more prevalent than by our present technic in which the child is studied
Vesicoureteral Reflux -Hutch et al.
FIG. 1. Case I. An eighteen year old girl who had been in good health except for occasional headaches was found to have hypertension (blood pressure 220/100 mm. Hg) on a routine physical examination. The urine was infected with Escherichia coli. Intravenous pyelograms failed to show excretion on the left. Differential function tests showed 3 per cent phenolsulfonphthalein excretion in thirty minutes on the left, 15 per cent on the right, and retrograde pyelograms showed atrophy of the left kidney. Cinefluorography showed bilateral reflux without ureteral dilatation and complete emptying of the bladder. pyelogram showing bilateral chronic A, retrograde pyelonephritis. B, single frame from the movie taken during voiding (cinefluoroscopy) showing bilateral reflux into undilated ureters. C, illustrative drawing of B.
at a time when he is clinically well. From this accumulating knowledge about reflux in children it can be concluded that reflux is demonstrable in half of the children with recurring urinary tract infections and undoubtedly is
present in even a larger percentage of these children. It is conceivable that reflux is present intermittently in nearly all of these children. Demonstration of RefEux in Adults with ,Vonobstructiue Pyelone$hritis. Now let us turn our attention to the available information about reflux in adults. In our own experience with cinefluoroscopy at the University of California [78-201 we have demonstrated reflux in many adults with various kinds of urinary tract infection. Of special interest is a group of twenty-two patients with acute recurring or chronic pyelonephritis, with normal-sized ureters and renal pelves (as judged by intravenous pyelography), in whom we have demonstrated reflux by cystography and/or cinefluoroscopy. These cases are summarized in Table II. Recently, Hodson and Edwards [8] reported twenty cases of reflux pyelonephritis in which the intravenous pyelograms revealed the x-ray appearance of nonobstructive pyelonephritis, and the cystograms revealed reflux. Eight of these patients were adults. They also investigated ten patients under treatment for chronic non-obstructive pyelonephritis (unilateral or bilateral) and were able to demonstrate reflux into the involved kidney (or kidneys) in nine of the ten patients. Williams [27] studied sixteen adults with nonobstructive pyelonephritis and found reflux in three. Recently, Milliez et al. [22] investigated ninety-five patients with hypertension and found reflux in nine. They noted that the greatest incidence of reflux occurred in hypertensive patients with previous attacks of pyelonephritis, recent enuresis or renal pain associated with a full bladder and relieved by voiding. Noix [23] also stresses the importance of checking hypertensive patients for reflux. In adults as well as in children a normal cystoscopic examination and normal pyelogram do not rule out the possibility of reflux. Therefore, a urologic study which is complete by present standards misses the reflux which is perpetuating the pyuria or bacteriuria. Even if a cystogram is obtained and reflux is not present, we cannot be certain that intermittent reflux is not the cause of the urinary tract infection. For example, we recently studied a thirty year old woman with recurring urinary tract infections. Urologic studies performed three years ago and one year ago both revealed a normal urinary tract. On the third examination a four-film cystogram was performed which revealed reflux into the lower third of the undilated right ureter AMERICAN
JOURNAL
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MEDICINE
Vesicoure teral Reflux-Hutch
et al.
FIG. 2. Case m. A thirty-two year old woman who began to have intermittent attacks of chills, fever and pyuria at age twenty-two. She had no associated history of attacks of cystitis and no definite kidney pain. The blood urea nitrogen was 16.7 mg. per cent and blood pressure lZO/SS mm. Hg. Urine culture showed Escherichia coli. Urinalysis revealed intermittent pyuria. Intravenous and retrograde pyelograms showed an atrophic chronic pyelonephritic kidney on the left and a chronic pyelonephritic kidney on the right. The cystogram revealed reflux into the left undilated ureter and kidney. A, intravenous pyelogram showing poor visualization bilaterally. B, retrograde pyelogram showing an atrophic chronic pyelonephritic (hypoplastic) kidney on the left and a chronic pyelonephritic kidney on the right. A cystogram reveals left reflux into an undilated ureter. Reflux could not be demonstrated on the right. The failure to demonstrate reflux does not rule out the existence of reflux at some time in the past.
on one film only. Cinefluoroscopy failed to demonstrate this reflux. This is not one isolated example, as it has been observed many times in both children and adults. It leaves one with the belief that reflux may be present even when our most sensitive tests fail to reveal it. The observation noted in the discussion of reflux in children, that reflux may be present when the urinary tract is infected and disappear after the infection is cured, is just as valid in adults, leading to the disquieting conclusion that reflux is often missed by studying these patients when they are clinically well. Many children and some adults cannot void during the cystogram, yet in some patients reflux occurs only during voiding. Undoubtedly this fact causes us to miss many cases of reflux even when we look for it. Residual Urine May Represent Refrux Rather Than Vesical Neck Obstruction. Urologists who believe that bladder neck obstruction is the cause of reflux and recurring urinary tract infections have pointed to the demonstration of residual urine as the irrefutable proof of their belief. However, cinefluoroscopy shows that the great majority of these patients empty their bladders completely but that the bladder is refilled after VOL.
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voiding by the return of refluxed urine from the ureters. The concept of bladder neck obstruction implies that a high intravesical pressure is present and that this causes the disease of the upper urinary tract. Efforts to demonstrate this abnormally high intravesical pressure in children with recurring urinary tract infections without obvious obstruction have failed [24-261. Our own demonstration of low pressure reflux* in many children who do not demonstrate reflux during voiding (high pressure) further weakens the position of those who insist that reflux is a product of high intravesical pressure secondary to bladder neck obstruction
[271*
Rejlux Is Being Demonstrated in Diseases in which Its Presence Had Not Been Suspected. As studies of vesicoureteral reflux are being extended, new correlations with a number of urinary tract diseases are evolving. For example, several workers [8,1 I, 78,79,21,28] have been impressed with the high incidence of reflux in atrophic or * Low pressure reflux is a term used to describe reflux which occurs early in the voiding cycle, as the bladder is just beginning to fill and when the intravesical pressure is at its lowest point.
Vesicoureteral
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FIG. 3. Case v. A fifty-eight year old woman who had excretory urograms ten years earlier as part of a routine investigation of lumbosacral back pain and pyuria. The urograms showed atrophy of the right kidney. Cystoscopy
in 1961 showed a gaping right ureteral orifice. Retrograde pyelograms confirmed the findings of the previous excretory urograms. Cinefluorography showed reflux up an undiiated right ureter. After a right nephroureterectomy, her course was uneventful. Pathologic examination of the removed kidney showed marked atrophic pyelonephritis. A, retrograde pyelogram showing an atrophic chronic pyelonephritic (hypoplastic) kidney on the right with a normal appearing left kidney which has undergone compensatory hypertrophy. B, cine-
fluoroscopy reveals reflux illustrative drawing of B.
into
the
right
ureter.
C,
et al.
FIG. 4. Case IX. A thirty-four year old woman who had some symptoms of urinary tract disease in childhood, but no further trouble until eight years ago when she had three bouts of pyelonephritis during her first pregnancy. Intravenous pyelograms taken at that time were normal. Her urine has been infected for the last year in spite of therapy. Recent intravenous pyelograms, when compared with previous ones, showed a decrease in size of both kidneys, especially on the right, without ureteral dilatation. Cystoscopic examination showed large, gaping orifices. Cinefluoroscopy showed bilateral reflux into undilated ureters. A, intravenous pyelogram showing bilateral chronic pyelonephritis. B, cinefluoroscopy reveals bilateral reflux. C, illustrative drawing of B.
hypoplastic kidneys in both children and adults. We [19] have suggested that these small kidneys may be the result of overwhelming infection secondary to reflux which occurs in early neonatal life. As a result, the kidney ceases to grow and remains the size it was when the AMERICAN
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FIG. 5. Case XII. A twenty-eight year old woman who had no history of urinary tract disease until one year ago. At that time she had a severe attack of pyelonephritis on the left side. During the last year she had six recurrences. The bladder emptied normally, but her urine was infected intermittently. Intravenous pyelograms were normal except for some slight pyelonephritic changes in the upper calyx on the left side. The cystogram revealed left reflux. A, intravenous pyelogram showing early pyelonephritic changes on the left side. B, cystogram reveals reflux into an undilated left kidney and ureter. This reflux was present only on the immediate film of the cystogram.
infection occurred. If this occurs bilaterally and is not fatal, it produces the clinical picture of renal rickets. Hodson and Edwards [8] examined eight patients with renal rickets and found reflux in six. We have suggested also that reflux may be an etiologic factor in obstruction of the ureteropelvic junction [19]. According to Hanley [29], about 15 per cent of normal renal pelves are of the “closed” type. They can effect the transport of urine under normal conditions, but under conditions of overhydration they cannot rid themselves of the increased amount of urine that is formed and, as a result, begin to dilate. Given this type of renal pelvis, together with reflux early in life, it is suggested that refluxed urine could produce the overload needed to dilate the renal pelvis permanently in the manner that we now accept as typical of primary obstruction of the ureteropelvicjunction. Reflux has been demonstrated in a number of patients who complain of renal pain when their bladder is full and whose pain is relieved by voiding. A few patients who complain of renal pain during voiding have been shown to have reflux. VOL. 34,
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The Concept of Maturation of the Intravesical Ci-eter. It is agreed generally that the ease with which a ureterovesical valve may be made incompetent varies inversely with the length of the intravesical segment of the ureter, or conversely, the shorter the intravesical segment, the greater is the tendency for reflux to develop in it. Hutch [30] has found that at birth the intravesical segment measures about 5 mm.; in adults it averages about 13 mm. He also found that the adult length of the intravesical ureter is achieved at about twelve years of age. This explains why reflux is more common in children than in adults and presumably accounts for the clinical observation that many children who have recurring urinary tract infections seem to recover spontaneously about the time of puberty. Association Between Urinary Tract Infections in Children and Pyelonephritis in Adults. As more information becomes available, it is increasingly evident that there is a direct relationship between urinary tract infections in children and adults. Jawetz [31] has proposed that the individual attack of acute pyelonephritis should be viewed as an episode in a prolonged disease
Vesicoureteral
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6B
FIG. 6. Case XIII. A sixteen year old girl had recurring attacks of upper abdominal pain, chills, fever and fatigue all her life. At age seven intravenous pyelograms showed bilateral pyelonephritis, and at age eleven a cystogram showed bilateral reflux. Her left kidney was removed surgically and proved to be a small pyelonephritic kidney weighing only 41 gm. Her infections persisted and a recent study by cinefluoroscopy revealed reflux into the remaining kidney and reflux into the left ureteral stump. These roentgenograms were made prior to the left nephrectomy. A, intravenous pyelogram showing bilateral chronic pyelonephritis. The left kidney has undergone atrophy. B, cystogram reveals reflux into the left ureter and kidney and into the right lower ureter.
process rather than as an isolated event. Hutch [5l has presented a hypothesis in which he attempts to explain the natural history of urinary tract infection on the basis of the status of the ureterovesical junction and the ease with which bacteria may reach the bladder in each age group in each sex. The common urinary tract infections in children occur predominantly in girls and usually take the form of pyelonephritis rather than cystitis. The high incidence of infection is explained by the short urethra and poor hygiene of the child: the sex predilection for girls (9:l) by the short female urethra. The high incidence of pyelonephritis is the result of the combination of frequent bladder infections and the short immature intravesical ureter of
the child, leading to reflux of infected bladder urine to the kidney. Many patients who have repeated attacks of pyelonephritis during early childhood seem to recover by themselves in late childhood or early adolescence. This presumably is because hygiene improves and the intravesical ureter elongates with maturity. During adolescence practically no new cases of pyelonephritis develop. These few teen-age patients whom we do see are holdovers from a severe form of the childhood disease. As the girl begins to lead a sexual life, cystitis again becomes common. Usually the adult ureterovesical junction can confine the infection to the bladder, but in some patients who have a short intravesical ureter or a damaged ureterovesical junction AMERICAN
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Vesicoureteral Reflux--Hutch et al. from childhood, reflux occurs, producing intermittent attacks of acute pyelonephritis or chronic pyelonephritis. In late adult life pyelonephritis becomes predominantly a disease of males because of the urinary obstruction caused by the enlarging prostate. This is due to structural damage to the ureterovesical junction as the bladder muscle strains to void. Reflux and pyelonephritis result. This accounts for the autopsy finding that pyelonephritis is as common in men as in women. Surgical Correction of Reflux. It is beyond the scope of this paper to discuss the technical aspects of the surgical correction of reflux. However, experience with the surgical correction of reflux has strengthened the hypothesis which considers vesicoureteral reflux to be a causative factor in upper urinary tract infection. Technics have been developed by which reflux can be corrected successfully in a high percentage of patients without damage to the upper urinary tract [32-381. In patients with reflux and recurring urinary tract infection, surgical correction of the reflux usually stops the recurring attacks of chills, fever and kidney pain, and the urine becomes sterile [28,36,38-G]. These results seem to warrant the conclusion that correction of the reflux is a specific treatment. Non-clinical Research on Vesicoureteral Rejlux. Almost all the investigative work on vesicoureteral reflux has been carried out in human subjects, thus obviating the doubt that always exists when the results of animal experiments are applied to human disease. Excellent non-clinical studies of reflux have been carried out in experimental animals and cadavers. Much has been learned about the anatomy of the ureterovesical junction and how it functions as a valve [44-471. Studies in different species reveal a high incidence of reflux in most laboratory animals [48-571. Studies of the comparative anatomy of the trigone and intravesical ureter show that the ease with which reflux occurs in these animals varies inversely with the length of the intravesical ureter and the development of the trigone [48,49]. Reflux can be produced experimentally by cutting the bladder muscle behind the intravesical ureter [&I, enlarging the ureteral orifice [48], cutting Waldeyer’s sheath [46], injecting fluid around the intravesical ureter [SO] and putting foreign bodies in the bladder [57]. Recently, Vivaldi and co-workers [52] injected bacteria (Proteus vulgaris) into the bladders of anesthetized white rats through a VOL.
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suprapubic incision. Fifteen of the twenty-five rats sacrificed two to thirty days later were found to have acute pyelonephritis. To prove that the bacteria were reaching the kidney through the ureter, the left ureter in a group of thirty-four rats was ligated surgically. When the bacteria were injected into the bladders in this group of rats, the left kidney was protected from bacterial invasion in all cases. Sommer [53] added an additional experiment by exposing the bladder and both ureters surgically in anesthetized white rats. He then filled the bladder with indigo carmine and observed the ureters for fifteen minutes. In seventeen of twenty rats so treated, reflux of the blue dye into the ureters occurred. Sommer concluded that the rat was not a good experimental animal for the study of urinary tract infections. How Refux May Perpetuate Urinary Tract Infection. A normal unobstructed bladder rids itself of bacteria by two mechanisms shown experimentally by Cox and Hinman [54]. One, the mechanical emptying of the bladder, rids it of the major portion of the bacteria but does not reduce the bacterial population to zero. The microorganisms remaining in the small amount of urine which wets the lining of the bladder even after complete voiding are eradicated by the intrinsic defense mechanisms of the vesical mucosa . When obstruction is present at the bladder neck or in the urethra, the bladder loses its ability to empty itself completely. If bacteria are introduced into the bladder under these conditions, the remaining volume of infected urine will be too great for the intrinsic defense mechanism of the bladder to eradicate the bacteria and infection will be established. Infection may perpetuate itself in an unobstructed urinary tract if reffux is occurring. Even though the bladder empties completely, it will be partially refilled by the infected, refluxed urine returning from the ureter. This likewise will overwhelm the intrinsic defense mechanisms of the bladder. Although bladder neck obstruction and vesicoureteral reflux are different pathologic processes, each perpetuates urinary tract infection in the same basic manner, namely, by making it difficult for the urinary tract to rid itself of infected urine. Vesicoureteral reflux is additionally dangerous because it supplies the route of access for the bacteria to reach the kidneys.
Vesicoureteral
Reflux -Hutch
COMMENTS
The wide application of the quantitative culture of voided urine has provided a useful tool in the study of the epidemiology of urinary tract infections. The method distinguishes contamination from active infection of the urinary tract, and through its use Kass and others [I] have shown that significant infection of bladder urine is fairly common in asymptomatic women. By assumption, the term bacteriuria has become almost synonymous with pyelonephritis but this obviously is not true. We wish to emphasize that a positive culture of bladder urine means only that the bladder urine is infected. It does not tell us whether the infection is limited to the bladder or involves the kidney as well; nor does it tell us whether the infection reaches the bladder from an external source through the urethra or from the kidney through the ureter. Many children with recurring and chronic pyelonephritis have been studied for reflux. With the most advanced equipment (cinefluoroscopy), reflux can be demonstrated in nearly half of these children. Relatively few adults with pyelonephritis have been studied in this way, but early results indicate that many of them may have reflux. We have included a review of twenty-two of our own patients with non-obstructive pyelonephritis in each of whom reflux has been demonstrated. We have shown how an infection can be perpetuated in an unobstructed urinary tract if vesicoureteral reflux is present. The significance of these interrelated observations is that if reflux is the cause of non-obstructive pyelonephritis, surgical correction of the reflux may prevent further progression of the disease. Our efforts in the immediate future should be directed toward two objectives: (1) to demonstrate the frequency of reflux in adults with non-obstructive pyelonephritis, and (2) to determine whether or not pyelonephritis, in a patient in whom reflux has been demonstrated, can be prevented by surgical correction of the reflux. SUMMARY
Vesicoureteral reflux is being demonstrated increasingly, not only in children who have intermittent bouts of acute pyelonephritis, but also in adults with chronic non-obstructive pyelonephritis. We present twenty-two of our own patients, all adults with recurring or chronic non-obstructive pyelonephritis, in each of whom reflux has been demonstrated.
et al.
Reflux may be intermittent, hence, a negative cystogram does not rule it out. Normal intravenous pyelograms frequently are found in patients with ureteral reflux. Residual urine may represent return of refluxed urine to the bladder rather than vesical neck obstruction. Reflux may be the cause of atrophic pyelonephritis; it may be a factor in obstruction of the ureteropelvic junction and may explain abdominal pain after voiding. The ease with which reflux occurs in the human ureterovesical valve changes with the sex and age of the patient and closely parallels the natural history of pyelonephritis. Animal experiments demonstrate the valvular mechanisms involved in the prevention of reflux. Reflux perpetuates infection by overloading the intrinsic bladder defense mechanism immediately after evacuation of the bladder, by the return of the infected urine to the bladder. Surgical correction of reflux stops the clinical attacks of pyelonephritis and sterilizes the urine. Since asymptomatic infection of the bladder urine has been shown to be more common than previously believed, and since reflux is being demonstrated with increasing frequency, the detection and treatment of reflux may lead to a better understanding of the pathogenesis and treatment of chronic nonobstructive pyelonephritis. REFERENCES
1. QUINN, E. L. and KASS, E. H. Biology of Pyelonephritis. Boston, 1960. Little, Brown & Co. 2. MCGOVERN, J. H., MARSHALL, V. F. and PAQUIN, A. J.. JR. Vesicoureteral reguraitation in children J. Ural., 83: 122, 1960. - 3. STEWART, C. M. Delayed cystograms. J. Ural., 70: 588, 1953. 4. BUNGE, R. G. Delayed cystograms in children. J. Ural., 70: 729, 1953. 5. HUTCH, J. A. Role of the ureterovesical junction in the pathogenesis of pyelonephritis. J. Ural., 88: 354, 1962. 6. Panel discussion on vesicoureteral reflux in children. J. Ural., 85: 119, 1961. 7. MARSHALL, F. C. Excretory urographic changes in children which suggest occurrence of reflux. J. Ural., 87: 681, 1962. 8. HODSON, C. J. and EDWARDS, D. Chronic pyelonephritis and vesicoureteral reflux. Clin. Rndiol., 11: 219, 1960. 9. CAMPBELL, M. Clinical Pediatric Urology. Philadelphia, 1951. W. B. Saunders Co. 10. ST. MARTIN, E. C., CAMPBELL, J. H. and PASQUIER, C. M. Cystography in children. J. Ural., 75: 151, 1956. AMERICAN
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11. KJELLBERG, S. R., ERICSSON,N. D. and RUDHE, U. The Lower Urinary Tract in Childhood. Chicago, 1957. Year Book Publishers, Inc. 12. FORSYTHE,W. J. and WALLACE, I. R. Investigation and significance of persistent and recurring urinary tract infections in children. Brit. J. Ural., 30: 297, 1958. 13. PALKEN, M. and KENNELLY, J., JR. Recurrent urinary tract infections in girls. J. l/rol., 83: 745, 1960. 14. GROSS, K. E. and SANDERSON,S. S. Cineurethrography and voiding cinecystography with special attention to vesicoureteral reflux. Radiology, 77: 573, 1961. 15. HUTCH, J. A., HINMAN, F., JR. and MILLER, E. R. Unpublished data. 16. THOMPSON,I. Personal communication. 17. HANLEY, H. G. Transient stasis and reflux in the lower ureter. &it. J. Ural.. 34: 283, 1962. 18. HINMAN, F., JR. and HUTCH, J. A. Atrophic pyelonephritis from ureteral reflux without obstructive signs. .J. lirol., 87: 230, 1962. 19. HUTCH, J. A., HINMAN, F.. JR. and MILLER, E. R. Reflux as a cause of hydronephrosis and chronic pyelonephritis. J. Ural., 88: 169, 1962. 20. HUTCH. .I. A., HINMAN, F., JR. and MILLER, E. R. Unpublished data. 21. WILLIAMS, D. I. Megacystis and megaureter in children. Bull. New York Acad. Med., 35: 317, 1959. 22. MILLIEZ, P., LAGRUE, G., SAMARCO, P., NOIX, M. and BINET, J. L. Functional signs which cause suspicion of ascending pyelonephritis. Rro. Med. Moyen Orient, 17: 71, 1960. 23. NOIX, M. Cysto-urethral motricity in the course of micturition, its radiocinematography study. Arta urol. belg., 28: 532, 1960. 24. MACKELLER, A. and STEPHENS, F. D. Vesical diverticula in children. Australian @ New Zealand J. Surg., 30: 20, 1960. 25. STEPHENS,F. D. and LENAGHAN,D. The anatomical basis and dynamics of vesicoureteral reflux. J. Ural., 87: 669, 1962. 26. GARRETT, R. A., RHAMY, R. K. and CARR, J. R. Non-obstructive vesicoureteral regurgitation. J. IJrol., 87: 350, 1962. 27. HINMAN, F., JR., MILLER, E. R., HUTCH, J. A., GAINEY, M. D., Cox, C. E. and GOODFRIEND, R. B. Low pressure reflux. J. Ural., in press. 28. JOHNSTON,J. H. Vesico-ureteral reflux: its anatomical mechanism, causation, effects and treatment in the child. Ann. Roy. Coil. Surgeons England, 30: 324, 1962. 29. HANLEY, H. G. The pelviureteric junction: a cinepyelography study. Brit. J. lirol., 31: 377, 1959. 30. HUTCH, J. A. Theory of maturation of the intravesical ureter. J. IJrol., 86: 534, 1961. 31. JAWETZ, E. Urinary tract infections. Disense-aMonth, November 1954. 32. HUTCH, J. A. Vesicoureteral reflux in paraplegics: cause and correction. J. Ural., 68: 457, 1952. 33. HUTCH, J. A., BUNGE, R. G. and FLOCKS, R. H. Vesicoureteral reflux in children. J. Ural., 74: 607, 1955. 34. BISCHOFF,P. F. and BUSCH, H. G. Origin, clinical experiences and treatment of urinary obstructions VOL.
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