June 1975
998
The Journal o f P E D I A T R I C S
Vesicoureteral reflux and renal scarring
L E W Y AND B E L M A N ' S 1 paper on the familial occurrence of nonobstructive vesicoureteral reflux with renal scarring again raises questions about the significance of vesicoureteral reflux, and the causal relationship between it and atrophic pyelonephritis. Stewart,2, 3in 1949, reported inconstant vesicoureteral reflux in a series of roentgenograms made to demonstrate the bladder. Prior to these observations, it had generally been assumed that pyelitis and pyelonephritis resulted from lymphatic spread of infection from the perirectal area to the kidneys. Vesicoureteral reflux seemed to explain the pathogenesis of pyelonephritis 'and to show its relationship to recurrent urinary tract infections. Reflux was believed to permit bacteria to reach the kidneys from the bladder and provide stasis of urine which allowed bacteria to multiply and establish focal inflammation, thus providing conditions necessary to sustain infection. The short female urethra and "poor hygiene" allowed bacteria to enter the bladder from the perineum. Vesicoureteral reflux can be demonstrated in 50-60% of girls with recurrent pyuria. This figure is even higher in girls examined during acute episodes of urinary tract infection or pyuria. Hodson 4 reported focal renal scarring in some individuals with pyuria and vesicoureteral reflux. These observations and h y p o t h e s e s suggest that uncorrected, persistent vesicoureteral reflux can lead to chronic pyelonephritiS, atrophic destruction of kidneys, and death. Available data fail to support this thesis. Although pyuria is primarily a disease affecting girls, at no age do more girls or women die from renal disease than their male peers. Necropsy evidence of chronic pyelonephritis is equal in males and females. Focal renal scarring does occur in some children with vesicoureteral reflux. Its incidence is unknown since few longitudinal studies of large numbers of children with untreated vesicoureteral reflux are available. The need is to identify which kidneys are at risk from reflux so that appropriate therapeutic measures can be ~instituted. The frequent coexistence of pyuria and reflux, a n d the a l m o s t c o n s t a n t a s s o c i a t i o n o f m a s s i v e
Vo186. No. 6, pp. 998-1000
vesicoureteral reflux with atrophic kidneys, complicate the problem. The causal relationship between reflux and atrophic pyelonephritis has not been proved. Renal scarring may occur on one side only in children with bilateral vesicoureteral reflux; it may occur either on the ipsilateral or contralateral side of reflux in the presence of unilateral reflux, while the other kidney remains normal. The results of corrective genitourinary surgery in general have not been outstanding. VY-plasties for "bladder outlet obstructions" and urethral meatotomies for "urethritis" and "meatal stenosis" in girls are two examples of once widely used surgical procedures which have now been virtually abandoned as therapeutic measures for overdiagnosed conditions of rare occurrence. Does antireflux surgery deserve the same fate? See related article, p. 851. The indications for voiding cystourethrography have not been established. If vesicoureteral reflux is not a common precursor of renal scarring and atrophy, what is the value of its roentgen demonstration? Cystourethrography can demonstrate vesicoureteral reflux and obstructive lesions of the lower urinary tract. It can show distensibility of ureters and pelvocalyceal systems and reinforce our appreciation that these structures are neuromuscular tubes which are not rigid, enabling us better to evaluate the findings on excretory urograms. The vagaries of reflux must literally be seen to be appreciated. Reflux may occur early during the course of bladder filling, as the bladder is being distended, or when it contracts during voiding. To these different times of filling, descriptive terms of "low," "average," and "high pressure" reflux have been applied. Their importance in different individuals is speculative and not proved. One of our patients showed massive unilateral vesicoureteral reflux as her bladder was being filled. After she had voided, contrast material emptied from the ureter and pelvocalyceal s y s t e m on the side of reflux, entered the bladder, and promptly flowed into
Volume 86 Number 6
the contralateral ureter. Reflux may be present early d u r i n g filling at one e x a m i n a t i o n , in t h e late filling phase in another, both early and late on a third, and may be absent on a fourth examination. Reflux can be unpredictable, uneven, and erratic. No group of children with vesicoureteral reflux has b e e n studied on consecutive days to demonstrate variations in the patterns of reflux. Moreover, an adequate n u m b e r of normal children has not been investigated to determine the incidence of reflux in the normal population. T h e v o i d i n g c y s t o u r e t h r o g r a m s e e m s to d e t e c t a group of children at risk from increasing morbidity of recurring urinary tract infections. Perhaps children with r e f l u x s h o u l d be followed m o r e c a r e f u l l y m e d i c a l l y . Antireflux surgery may be effective in reducing unacceptable morbidity in selected children in whom medical treatment has been unsuccessful. What of the m a n a g e m e n t of familial reflux? Should each member of the family of the child with vesicoureteral reflux have cystography and excretory urography? A sensible answer is "no." We do not understand the significance of vesicoureteral reflux; its demonstration in children with normal renal function and sterile urine may further cloud the issue. It seems proper to investigate the family of any child found to have renal failure, or any family in which two or more m e m b e r s have renal disease of any kind. In such cases, excretory urography is a reasonable method o f radiographic investigation, with cystography carried out later if abnormal changes are observed on these films. The importance and role of vesicoureteral reflux in progressive renal disease are unanswered. Blank 5 compares observations here to those of " R a s h o m o n . " Each observer sees the same things and interprets them differently. Filly and associates 6 reported "the developm e n t and progression of clubbing and scarring in children with recurrent urinary tract infections." Seeking to show the relatively high incidence of progressive scarring of kidneys which were previously normal, they reported that two of 15 normal kidneys not associated with vesicoureteral reflux became clubbed and scarred; two of 16 normal kidneys with vesicoureteral reflux developed similar changes. In one child without vesicoureteral reflux whose kidney had become scarred, cystoscopy showed "gaping orifices" suggesting that reflux "should have occurred" even though it was not observed on two separate voiding cystourethrograms. Sixteen of 24 abnormal kidneys with vesicoureteral reflux had progressive scarring after antireflux surgery. Thirteen normal kidneys with reflux remained normal after antireflux surgery. Fifteen of 24 kidneys with ab-
Editor's column
999
normal changes developed further shrinkage under medical management. The authors use these data to support the need for appropriate surgical or medical regimens to prevent damage to kidneys before the damage occurs. The same data also support other conclusions; namely, that in this group of patients, antireflux surgery was not effective in preventing renal damage after it had once become visible. N o available data support a high or different incidence of renal damage in previously normal kidneys with reflux as opposed to those without reflux. The basic problem remains the causal relationship, if any, b e t w e e n a t r o p h i c p y e l o n e p h r i t i s and vesicoureteral reflux. Blank and Girdany's 7studies showed three things clearly. (1) Rarely was focal scarring identified in an otherwise normal kidney associated with vesicoureteral reflux: Only one of 87 girls followed for more than five years after being initially observed because of pyuria and vesicoureteral reflux had some slight loss of renal parenchyma. (2) Small s h r u n k e n kidneys, when found, were present at the time the children were first examined, and in Blank and Girdany's 7series, these changes did not progress during prolonged medical observation or after antireflux surgery. These changes did progress in Filly and associates 6 patients, w h e t h e r the c h i l d r e n were t r e a t e d m e d i c a l l y or surgically. (3) The course of atrophic pyelonephritis, chronic renal disease, is not marked by recurring episodes of fever and pyuria. Rather, as in the propositus case presented by Lewy and Belman, 1 renal failure had a slow and insidious onset. Ellis 8 wrote, "Chronic pyelonephritis is difficult to recognize clinically, for only rarely is there a history of symptoms suggesting pyelitis, and in the late stage when these patients usually first come under observation, pus is often absent from the urine." Kleeman and associates 9 contrasted two groups of patients, those who have a "silenl but destructive course" and those who have many complaints with little evidence of kidney destruction. All 15 children at the Children's Hospital at Pittsburgh 7 with necropsy proved chronic pyelonephritis had a silent course, in contrast to the children with recurring urinary tract infections whose complaints included dysuria, fever, and pyuria. In Blank and Girdany's 7 words, " T h e infrequent occurrence of progressive dilatation of the calices and loss of parenchyma, the radiographic findings ascribed to chronic pyelonephritis, in the excretory urograms of children who have had pyuria and vesicoureteral reflux, suggests that reflux does not initiate, propagate, or necessarily accompany these changes. The different clinical
1000
Editor~ column
course o f children with microscopically diagnosed pyelonephritis implicates o t h e r u n k n o w n factors."
Bertram R. Girdany, M.D. Professor of, Radiology and Pediatrics University of Pittsburgh School of Medicine, and Director, Department of Radiology Children's Hospital of Pittsburgh Stuart E. Price, Jr., M.D. Clinical Assistant Professor of Urology University of Pittsburgh School of Medicine, and Director and Chief of Urology Children's Hospital of Pittsburgh REFERENCES 1. Lewy PR, and Belman AB: Familial occurrence of nonobstructive, sterile vesicoureteral reflux with renal scarring, J Pediatr 1975.
The JoumalofPediatrics June1975
2. Stewart CM: Personal communication. 3. Stewart CM: Delayed cystograms, J Urol 70:588, 1953. 4. Hodson J: Pyelonephritis in children, Ann Radiol (Paris) 7:355, 1964. 5. Blank E: Personal communication. 6. Filly R, Friedland G, Govan DE, and Fair WR: Development and progression of clubbing and scarring in children with recurrent urinary tract infections, Radiology 113:145, 1974. 7. Blank E, and Girdany BR" Prognosis with Vesicoureteral reflux, Pediatrics 48:782, 1971. 8. Ellis A: Natural history of Bright's disease, Lancet 1:72, 1942. 9. Kleeman CR, Hewitt WL, and Guze LB: Pyelonephritis, Medicine 39:3, 1960.
998
The Journal o f P E D I A T R I C S
Vesicoureteral reflux and renal scarring
L E W Y AND B E L M A N ' S 1 paper on the familial occurrence of nonobstructive vesicoureteral reflux with renal scarring again raises questions about the significance of vesicoureteral reflux, and the causal relationship between it and atrophic pyelonephritis. Stewart,2, 3in 1949, reported inconstant vesicoureteral reflux in a series of roentgenograms made to demonstrate the bladder. Prior to these observations, it had generally been assumed that pyelitis and pyelonephritis resulted from lymphatic spread of infection from the perirectal area to the kidneys. Vesicoureteral reflux seemed to explain the pathogenesis of pyelonephritis 'and to show its relationship to recurrent urinary tract infections. Reflux was believed to permit bacteria to reach the kidneys from the bladder and provide stasis of urine which allowed bacteria to multiply and establish focal inflammation, thus providing conditions necessary to sustain infection. The short female urethra and "poor hygiene" allowed bacteria to enter the bladder from the perineum. Vesicoureteral reflux can be demonstrated in 50-60% of girls with recurrent pyuria. This figure is even higher in girls examined during acute episodes of urinary tract infection or pyuria. Hodson 4 reported focal renal scarring in some individuals with pyuria and vesicoureteral reflux. These observations and h y p o t h e s e s suggest that uncorrected, persistent vesicoureteral reflux can lead to chronic pyelonephritiS, atrophic destruction of kidneys, and death. Available data fail to support this thesis. Although pyuria is primarily a disease affecting girls, at no age do more girls or women die from renal disease than their male peers. Necropsy evidence of chronic pyelonephritis is equal in males and females. Focal renal scarring does occur in some children with vesicoureteral reflux. Its incidence is unknown since few longitudinal studies of large numbers of children with untreated vesicoureteral reflux are available. The need is to identify which kidneys are at risk from reflux so that appropriate therapeutic measures can be ~instituted. The frequent coexistence of pyuria and reflux, a n d the a l m o s t c o n s t a n t a s s o c i a t i o n o f m a s s i v e
Vo186. No. 6, pp. 998-1000
vesicoureteral reflux with atrophic kidneys, complicate the problem. The causal relationship between reflux and atrophic pyelonephritis has not been proved. Renal scarring may occur on one side only in children with bilateral vesicoureteral reflux; it may occur either on the ipsilateral or contralateral side of reflux in the presence of unilateral reflux, while the other kidney remains normal. The results of corrective genitourinary surgery in general have not been outstanding. VY-plasties for "bladder outlet obstructions" and urethral meatotomies for "urethritis" and "meatal stenosis" in girls are two examples of once widely used surgical procedures which have now been virtually abandoned as therapeutic measures for overdiagnosed conditions of rare occurrence. Does antireflux surgery deserve the same fate? See related article, p. 851. The indications for voiding cystourethrography have not been established. If vesicoureteral reflux is not a common precursor of renal scarring and atrophy, what is the value of its roentgen demonstration? Cystourethrography can demonstrate vesicoureteral reflux and obstructive lesions of the lower urinary tract. It can show distensibility of ureters and pelvocalyceal systems and reinforce our appreciation that these structures are neuromuscular tubes which are not rigid, enabling us better to evaluate the findings on excretory urograms. The vagaries of reflux must literally be seen to be appreciated. Reflux may occur early during the course of bladder filling, as the bladder is being distended, or when it contracts during voiding. To these different times of filling, descriptive terms of "low," "average," and "high pressure" reflux have been applied. Their importance in different individuals is speculative and not proved. One of our patients showed massive unilateral vesicoureteral reflux as her bladder was being filled. After she had voided, contrast material emptied from the ureter and pelvocalyceal s y s t e m on the side of reflux, entered the bladder, and promptly flowed into
Volume 86 Number 6
the contralateral ureter. Reflux may be present early d u r i n g filling at one e x a m i n a t i o n , in t h e late filling phase in another, both early and late on a third, and may be absent on a fourth examination. Reflux can be unpredictable, uneven, and erratic. No group of children with vesicoureteral reflux has b e e n studied on consecutive days to demonstrate variations in the patterns of reflux. Moreover, an adequate n u m b e r of normal children has not been investigated to determine the incidence of reflux in the normal population. T h e v o i d i n g c y s t o u r e t h r o g r a m s e e m s to d e t e c t a group of children at risk from increasing morbidity of recurring urinary tract infections. Perhaps children with r e f l u x s h o u l d be followed m o r e c a r e f u l l y m e d i c a l l y . Antireflux surgery may be effective in reducing unacceptable morbidity in selected children in whom medical treatment has been unsuccessful. What of the m a n a g e m e n t of familial reflux? Should each member of the family of the child with vesicoureteral reflux have cystography and excretory urography? A sensible answer is "no." We do not understand the significance of vesicoureteral reflux; its demonstration in children with normal renal function and sterile urine may further cloud the issue. It seems proper to investigate the family of any child found to have renal failure, or any family in which two or more m e m b e r s have renal disease of any kind. In such cases, excretory urography is a reasonable method o f radiographic investigation, with cystography carried out later if abnormal changes are observed on these films. The importance and role of vesicoureteral reflux in progressive renal disease are unanswered. Blank 5 compares observations here to those of " R a s h o m o n . " Each observer sees the same things and interprets them differently. Filly and associates 6 reported "the developm e n t and progression of clubbing and scarring in children with recurrent urinary tract infections." Seeking to show the relatively high incidence of progressive scarring of kidneys which were previously normal, they reported that two of 15 normal kidneys not associated with vesicoureteral reflux became clubbed and scarred; two of 16 normal kidneys with vesicoureteral reflux developed similar changes. In one child without vesicoureteral reflux whose kidney had become scarred, cystoscopy showed "gaping orifices" suggesting that reflux "should have occurred" even though it was not observed on two separate voiding cystourethrograms. Sixteen of 24 abnormal kidneys with vesicoureteral reflux had progressive scarring after antireflux surgery. Thirteen normal kidneys with reflux remained normal after antireflux surgery. Fifteen of 24 kidneys with ab-
Editor's column
999
normal changes developed further shrinkage under medical management. The authors use these data to support the need for appropriate surgical or medical regimens to prevent damage to kidneys before the damage occurs. The same data also support other conclusions; namely, that in this group of patients, antireflux surgery was not effective in preventing renal damage after it had once become visible. N o available data support a high or different incidence of renal damage in previously normal kidneys with reflux as opposed to those without reflux. The basic problem remains the causal relationship, if any, b e t w e e n a t r o p h i c p y e l o n e p h r i t i s and vesicoureteral reflux. Blank and Girdany's 7studies showed three things clearly. (1) Rarely was focal scarring identified in an otherwise normal kidney associated with vesicoureteral reflux: Only one of 87 girls followed for more than five years after being initially observed because of pyuria and vesicoureteral reflux had some slight loss of renal parenchyma. (2) Small s h r u n k e n kidneys, when found, were present at the time the children were first examined, and in Blank and Girdany's 7series, these changes did not progress during prolonged medical observation or after antireflux surgery. These changes did progress in Filly and associates 6 patients, w h e t h e r the c h i l d r e n were t r e a t e d m e d i c a l l y or surgically. (3) The course of atrophic pyelonephritis, chronic renal disease, is not marked by recurring episodes of fever and pyuria. Rather, as in the propositus case presented by Lewy and Belman, 1 renal failure had a slow and insidious onset. Ellis 8 wrote, "Chronic pyelonephritis is difficult to recognize clinically, for only rarely is there a history of symptoms suggesting pyelitis, and in the late stage when these patients usually first come under observation, pus is often absent from the urine." Kleeman and associates 9 contrasted two groups of patients, those who have a "silenl but destructive course" and those who have many complaints with little evidence of kidney destruction. All 15 children at the Children's Hospital at Pittsburgh 7 with necropsy proved chronic pyelonephritis had a silent course, in contrast to the children with recurring urinary tract infections whose complaints included dysuria, fever, and pyuria. In Blank and Girdany's 7 words, " T h e infrequent occurrence of progressive dilatation of the calices and loss of parenchyma, the radiographic findings ascribed to chronic pyelonephritis, in the excretory urograms of children who have had pyuria and vesicoureteral reflux, suggests that reflux does not initiate, propagate, or necessarily accompany these changes. The different clinical
1000
Editor~ column
course o f children with microscopically diagnosed pyelonephritis implicates o t h e r u n k n o w n factors."
Bertram R. Girdany, M.D. Professor of, Radiology and Pediatrics University of Pittsburgh School of Medicine, and Director, Department of Radiology Children's Hospital of Pittsburgh Stuart E. Price, Jr., M.D. Clinical Assistant Professor of Urology University of Pittsburgh School of Medicine, and Director and Chief of Urology Children's Hospital of Pittsburgh REFERENCES 1. Lewy PR, and Belman AB: Familial occurrence of nonobstructive, sterile vesicoureteral reflux with renal scarring, J Pediatr 1975.
The JoumalofPediatrics June1975
2. Stewart CM: Personal communication. 3. Stewart CM: Delayed cystograms, J Urol 70:588, 1953. 4. Hodson J: Pyelonephritis in children, Ann Radiol (Paris) 7:355, 1964. 5. Blank E: Personal communication. 6. Filly R, Friedland G, Govan DE, and Fair WR: Development and progression of clubbing and scarring in children with recurrent urinary tract infections, Radiology 113:145, 1974. 7. Blank E, and Girdany BR" Prognosis with Vesicoureteral reflux, Pediatrics 48:782, 1971. 8. Ellis A: Natural history of Bright's disease, Lancet 1:72, 1942. 9. Kleeman CR, Hewitt WL, and Guze LB: Pyelonephritis, Medicine 39:3, 1960.
