0022-5347 /92/1485-1758$03.00/0 Vol. 148, 1758-1760, November 1992
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
COMMENTARY: VESICOURETERAL REFLUX-1992 TERRY D. ALLEN, BILLY S. ARANT, JR. The landmark observations made 30 to 40 years ago by Hutch,1 and Hodson and Edwards 2 called attention to the important relationship between vesicoureteral reflux and renal scarring, and heralded the beginning of a new era in the management of chronic renal disease. Armed with the voiding cystourethrogram for diagnosis and a variety of new operations for the correction of reflux, we seemed on the verge of being able to make renal scars a lesion of historical interest only. However, in the interv-ening--years- an enormous amount of experimental and clinical data have modified our original, somewhat simplistic, concept of the problem and made us view the issue with greater equanimity. In the first place, it seems that we may have overestimated the importance of reflux in the etiology of pyelonephritis and renal scars. Not all patients with pyelonephritis have demonstrable reflux and the likelihood of renal scars developing as a consequence of pyelonephritis is the same regardless of whether reflux is documented. 3• 4 In fact, many patients with reflux never have a urinary tract infection at all,5 and ifpyelonephritis should occur it may do so on the nonrefluxing side. 4 Additionally, the mechanism by which reflux produces renal scars is still uncertain. There is no doubt that bacterial pyelonephritis produces renal scars experimentally3· 4 and clinically. 6 Dimercaptosuccinic acid scans have allowed us to follow sequentially the evolution of a scar from an area of decreased blood flow during the acute inflammatory phase to a parenchymal defect indicative of a mature scar. 4 Yet only about half of the patients with acute pyelonephritis will have such a scar. 4 Why is this the case? What converts an acute inflammatory process into a scar in some patients and not in others? Is it related to the magnitude of the pressure driving the organisms into the tissues, the intrinsic virulence of the organism itself, the host defense mechanisms or some other factor not yet identified? Furthermore, some of the worst examples of renal injury associated with reflux are those that are present at birth. Since renal damage at that time cannot be the consequence of infection, such injury is assumed to be developmental in origin but the pathophysiology of this is not entirely clear either. Are the reflux and the nephropathy merely separate expressions of a common developmental abnormality, or is there a cause and effect relationship operating in these cases? Sillen et al performed cystometry in 18 consecutive infants (16 boys and 2 girls) with gross bilateral reflux and found elevated voiding pressures in all but 1.7 Yeung et al studied 84 infants with reflux detected prenatally because of hydronephrosis and found increased bladder wall thickness in 24 of the boys. 8 These 2 studies suggest the possibility of transient bladder outflow obstruction with elevated intraluminal pressure, which might damage the kidneys during development; elevated intraluminal pressures are known to be able to produce renal scars indistinguishable from those caused by bacterial infection, especially in the young patient. 9· 10 It would be helpful to know to what extent these congenital renal changes account for the overall number of scars seen in association with reflux, and for this reason a good, noninvasive method to screen neonates for reflux and renal morphology would be of enormous value. Unfortunately, sonography will detect only reflux associated with dilatation of the collecting system and most other studies are invasive to some degree. A problem encountered in trying to resolve some of these issues is the difficulty in documenting the presence of a scar. Whether one uses the nephrogram from an excretory urogram, 11 a dimercaptosuccinic acid scan 4 or a 3-dimensional volume
AND
JAMES A. ROBERTS
scanner, 12 only relatively large scars can be seen and some of these become obvious only when growth of the surrounding normal parenchyma causes them to stand out in contrast. For this reason we may not be certain about scarring for several years until these changes become clearly defined. Smaller scars or subtle thinning of the renal parenchyma may represent injury beyond our ability to detect reliably with current techniques.13 However, the progressive decline in renal function noted by Berg following_pyelonephritis 14 a11d the_inexoI_able progression to renal failure in instances of advanced renal damage 15 remind us that no instance of renal injury should be taken lightly. Even some fundamental concepts regarding the etiology of reflux have gone through periods of revision. In early studies, many of which were based on static rather than voiding cystograms, it appeared that reflux in the human was categorically abnormal. Now it seems that a small percentage of otherwise normal infants may exhibit reflux, which usually resolves spontaneously within a few years. A similar phenomenon has been described in dogs 16 and in primates. 17 Another early concept about reflux was that it resulted from infravesical obstruction (bladder neck obstruction), which was consistent with the experimental production of reflux by banding the bladder neck. As this concept became discredited the pendulum swung to reflux as a primary ureterovesical anomaly. There is much evidence to support this philosophy; reflux may be identified prenatally by sonography, the incidence varies according to racial groups 18 and it shows a strong familial tendency indicative of a genetically transmitted disorder. 5 Yet the peak incidence in older children and the bimodal pattern of boys in infancy and girls later are not entirely consistent with a single etiology. 19 Current evidence favors a multifactorial origin for reflux: congenital in the infant and acquired, usually by voiding dysfunction, in the other child. An informed approach to the management of reflux requires a knowledge of its natural history. Thanks to the long-term studies of Smellie 20 and others 21 · 22 it is obvious that there is a tendency for reflux to resolve spontaneously with time but there is a decided difference in the rate of resolution depending upon the grade of reflux. The resolution rate of low grade reflux has been found to be as high as 85 % but this rate may be less than half of that for dilating reflux. 23 Across the board resolution of reflux averages about 50% in 5 years. Even when reflux persists, it usually declines in grade with time. Furthermore, there are fewer problems with recurrent urinary tract infections and fewer new scars appearing as the child grows older. There is concern about a recrudescense of pyelonephritis in women as they enter the sexually active and childbearing years but this too appears to have been overly stressed. Pyelonephritis of pregnancy does not correlate with reflux in the manner that might have been expected, and nowhere is there convincing evidence that correction of reflux by surgical intervention has any significant effect upon the incidence or severity of pyelonephritis of pregnancy. How, then, should reflux be treated? One indisputable point of agreement has been the importance of preventing secondary pyelonephritis. A major breakthrough in this regard has been the discovery that urinary tract infection and renal scars can generally be prevented by the use of continuous low dose prophylactic antibacterials. 23 Agents that are absorbed high in the gastrointestinal tract are best since they are the least likely to alter the colonic flora, the bacterial reservoir for future urinary tract infections. Nitrofurantoin and sulfamethoxazole-
1758
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VESICOURETERAL REFLUX-1992
trimethoprim preparations have been the most popular agents for this purpose but trimethoprim alone has proved satisfactory and may have fewer side effects. Prophylactic antibacterials not only seem to protect the urinary tract from the damage that pyelonephritis might cause but they also buy valuable time necessary to allow either the reflux to resolve spontaneously or the patient to reach an age when the clinical significance of the reflux is less. Another important concept that has surfaced has been that of prompt treatment whenever pyelonephritis develops. Several studies have shown that delay in the institution of treatment of pyelonephritis aggravates the resulting damage. 24 • 25 It is also apparent, although less clearly documented, that elevated intravesical pressure increases the extent of injury, so measures that might be undertaken to reduce these pressures should be encouraged. For dysfunctional voiding, which is a common condition in these patients, this may be as simple as initiating a program of bladder retraining. The role of ureteral reimplantation has not been as easy to define. There is general agreement that few indications exist for surgery in nondilating reflux. Secondary urinary tract infection in these patients is usually easily preventable by continuous antibacterial prophylaxis and the reflux generally resolves spontaneously anyway but there is less certainty about how to manage the higher grades of reflux. From the studies of Smellie20 and Bailey et al2 1 it is evident that long-term medical therapy is well tolerated and generally effective in preventing infection but reflux persists in many of these individuals and the threat of breakthrough infections, the risk of additional renal scarring and the need for supervision are psychologically debilitating for many patients. Surgical correction of reflux is successful in a high percentage of cases but complications do occur, and there is always the lingering suspicion that the patient might have fared as well without it. The International Reflux Study in Children was undertaken to resolve this dilemma by comparing outcomes in children with grades III and IV reflux randomized to medical or surgical treatment. This study has provided us with an enormous amount of information and some meaningful conclusions, although difficulties in making direct comparisons make some of the conclusions less than completely satisfying. For example, the incidence of urinary tract infection after initiation of treatment was the same in both groups but pyelonephritis occurred significantly less often in those treated surgically despite the fact that prophylactic antimicrobial agents were discontinued in the surgical group upon documentation that the reflux had been corrected successfully. 26 The incidence of new scars was also the same for both groups but those occurring in the surgical group generally appeared within 2 years after initiation of treatment, while those in the medical group continued to appear fairly evenly throughout followup. 27 The final conclusion of the study was that the outcome was similar whether medical or surgical therapy was selected but it would be of considerable interest to continue to follow these patients for an additional 5 years or more. Currently, it appears that the only absolute indication for surgical intervention remains failure of medical therapy but persistent reflux, breakthrough infections or simply the worry and expense of continued followup will probably drive many patients with higher grades of reflux to surgery before the debate is over. Superficially, the results of the attention and effort devoted to vesicoureteral reflux during the last 40 years might seem somewhat disappointing. It turns out that renal scars in patients with reflux may have been present from birth and, thus, not even preventable by current technology. Pyelonephritis is not always associated with reflux, nor does it always lead to scarring. Furthermore, correction of reflux may not necessarily prevent future infections. Both methods of treatment, medical and surgical, seem to work equally well. In fact, once reflux is identified and addressed appropriately it is unusual to see much
additional damage regardless of whether medical or surgical treatment is selected unless the kidney is heavily damaged at the outset, in which case a progressive decline in renal function can be expected regardless of how it is managed. In truth, the damage that occurs before reflux is recognized remains the single most important variable in the ultimate outcome of the disease process. A more positive view of the outcome of these labors is that they have directed our activities into ever more productive channels. They have convinced us, for example, that earlier recognition of reflux is essential for further therapeutic gains and sent us scurrying to find ways to screen for reflux at the beginning of life itself. They have also shown us that the enemy postnatally is pyelonephritis and perhaps elevated intraluminal pressures; vesicoureteral reflux is merely a vehicle, probably one of many, which facilitates the process. Finally, our findings have caused us to refocus our attention on the kidney, reminding us of the need for better understanding of the cellular events responsible for the parenchymal damage. International workshops in the future may discuss reflux only in passing while concentrating on such matters as bacterial virulence factors, host defense mechanisms, control of free oxygen radicals and even genetic engineering. We might summarize by saying that it is important to recognize reflux early, establish an effective therapeutic program promptly and follow the patient conscientiously. In most cases this will entail an initial program of prophylactic antibacterials and attention to factors, anatomical or functional, that lead to elevated intraluminal pressures or residual urine. For low grade reflux this is likely to be all that is required. For higher grades of persistent reflux consideration should be given to ureteral reimplantation as a legitimate alternative to long-term medical treatment. REFERENCES
1. Hutch, J. A.: Vesicoureteral reflux in the paraplegic: cause and correction. J. Urol., 68: 457, 1952. 2. Hodson, C. J. and Edwards, D.: Chronic pyelonephritis and vesicoureteric reflux. Clin. Rad., 11: 219, 1960. 3. Roberts, J. A.: Etiology and pathophysiology of pyelonephritis. Amer. J. Kidney Dis., 17: 1, 1991. 4. Rushton, H. G. and Majd, M.: Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J. Urol., part 2, 148: 1726, 1992. 5. Noe, H. N.: The long-term results of prospective sibling reflux screening. J. Urol., part 2, 148: 1739, 1992. 6. Winberg, J., Bollgren, I., Kallenius, G., Mollby, R. and Svenson, S. B.: Clinical pyelonephritis and focal renal scarring. A selected review of pathogenesis, prevention, and prognosis. Ped. Clin. N. Amer., 29: 801, 1982. 7. Sillen, U., Hjii.lmas, K., Aili, M., Bjure, J., Hanson, E. and Hansson, S.: Pronounced detrusor hypercontractility in infants with gross bilateral reflux. J. Urol., part 2, 148: 598, 1992. 8. Yeung, C. K., Dhillon, H. K., Duffy, P. G. and Ransley, P. G.: Vesicoureteric reflux in infants with prenatally diagnosed hydronephrosis. Read at annual meeting of Section on Urology, American Academy of Pediatrics, New Orleans, Louisiana, October 28, 1991. 9. Hodson, C. J., Maling, T. M. J., McManamon, P. J. and Lewis, M. G.: The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Brit. J. Rad., suppl., 13: 1, 1975. 10. Mendoza, J.M. and Roberts, J. A.: Effects of sterile high pressure vesicoureteral reflux on the monkey. J. Urol., 130: 602, 1983. 11. Smellie, J., Edwards, D., Hunter, N., Normand, I. C. S. and Prescod, N.: Vesico-ureteric reflux and renal scarring. Kidney Int., 8: 65, 1975. 12. Joseph, D. B., Young, D. W. and Jordan, S. P.: Renal cortical scintigraphy and single proton emission computerized tomography (SPECT) in the assessment of renal defects in children. J. Urol., part 2, 144: 595, 1990. 13. Bernstein, J. and Arant, B. S., Jr.: Morphological characteristics of segmental renal scarring in vesicoureteral reflux. J. Urol., part 2, 148: 1712, 1992.
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14. Berg, U. B.: Long-term followup of renal morphology and function in children with recurrent pyelonephritis. J. Urol., part 2, 148: 1715, 1992. 15. Jacobson, S. H., Eklof, 0. and Eriksson, C. G.: Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. Brit. Med. J., 299: 703, 1989. 16. Christie, B. A.: Incidence and etiology of vesicoureteral reflux in apparently normal dogs. Invest. Urol., 9: 184, 1971. 17. Roberts, J. A. and Riopelle, A. J.: Vesicoureteral reflux in the primate. II. Maturation of the ureterovesical junction. Pediatrics, 59: 566, 1977. 18. Askari, A. and Belman, A. B.: Vesicoureteral reflux in black girls. J. Urol., 127: 747, 1982. 19. King, L. R.: Vesicoureteral reflux: history, etiology and conservative management. In: Clinical Pediatric Urology. Edited by P. P. Kelalis and L. R. King. Philadelphia: W. B. Saunders Co., chapt. 11,pp. 342-365, 1976. 26. Smellie;--·J. !v1::--Reflections on -30-years-of treating childr-en \vith urinary tract infections. J. Urol., part 2, 146: 665, 1991. 21. Bailey, R. R., Lynn, K. L. and Smith, A. H.: Long-term followup of infants with gross vesicoureteral reflux. J. Urol., part 2, 148: 1709, 1992.
22. Rolleston, G. L., Shannon, F. T. and Utley, W. L. F.: Relationship of infantile vesicoureteric reflux to renal damage. Brit. Med. J., 1: 460, 1970. 23. Edwards, D., Normand, I. C. S., Prescod, N. and Smellie, J. M.: Disappearance of vesicoureteric reflux during long-term prophylaxis of urinary tract infection in children. Brit. Med. J., 2: 285, 1977. 24. Winberg, J., Bergstrom, T. and Jacobsson, B.: Morbidity, age and sex distribution, recurrences and renal scarring in symptomatic urinary tract infection in childhood. Kidney Int., 8: SlOl, 1975. 25. Winter, A. L., Hardy, B. E., Alton, D. J., Arbus, G. S. and Churchill, B. M.: Acquired renal scars in children. J. Urol., 129: 1190, 1983. 26. Jodal, U., Koskimies, 0., Hanson, E., Lohr, G., Olbing, H., Smellie, J. and Tamminen-Mobius, T.: Infection pattern in children with vesicoureteral reflux randomly allocated to operative or longterm antibacterial prophylaxis. J. Urol., part 2, 148: 1650, 1992. -27. 0-lbin-g, H.,--Claesson.,---L, Ebel,---K.-.D-.,-8eppanen1_lJ.; Smellie; fJ. __ M., Tamminen-Mobius, T. and Wikstad, I.: Renal scars and parenchymal thinning in children with vesicoureteral reflux: 5-year report of International Reflux Study in Children (European branch). J. Urol., part 2, 148: 1653, 1992.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
COMMENTARY: VESICOURETERAL REFLUX-1992 TERRY D. ALLEN, BILLY S. ARANT, JR. The landmark observations made 30 to 40 years ago by Hutch,1 and Hodson and Edwards 2 called attention to the important relationship between vesicoureteral reflux and renal scarring, and heralded the beginning of a new era in the management of chronic renal disease. Armed with the voiding cystourethrogram for diagnosis and a variety of new operations for the correction of reflux, we seemed on the verge of being able to make renal scars a lesion of historical interest only. However, in the interv-ening--years- an enormous amount of experimental and clinical data have modified our original, somewhat simplistic, concept of the problem and made us view the issue with greater equanimity. In the first place, it seems that we may have overestimated the importance of reflux in the etiology of pyelonephritis and renal scars. Not all patients with pyelonephritis have demonstrable reflux and the likelihood of renal scars developing as a consequence of pyelonephritis is the same regardless of whether reflux is documented. 3• 4 In fact, many patients with reflux never have a urinary tract infection at all,5 and ifpyelonephritis should occur it may do so on the nonrefluxing side. 4 Additionally, the mechanism by which reflux produces renal scars is still uncertain. There is no doubt that bacterial pyelonephritis produces renal scars experimentally3· 4 and clinically. 6 Dimercaptosuccinic acid scans have allowed us to follow sequentially the evolution of a scar from an area of decreased blood flow during the acute inflammatory phase to a parenchymal defect indicative of a mature scar. 4 Yet only about half of the patients with acute pyelonephritis will have such a scar. 4 Why is this the case? What converts an acute inflammatory process into a scar in some patients and not in others? Is it related to the magnitude of the pressure driving the organisms into the tissues, the intrinsic virulence of the organism itself, the host defense mechanisms or some other factor not yet identified? Furthermore, some of the worst examples of renal injury associated with reflux are those that are present at birth. Since renal damage at that time cannot be the consequence of infection, such injury is assumed to be developmental in origin but the pathophysiology of this is not entirely clear either. Are the reflux and the nephropathy merely separate expressions of a common developmental abnormality, or is there a cause and effect relationship operating in these cases? Sillen et al performed cystometry in 18 consecutive infants (16 boys and 2 girls) with gross bilateral reflux and found elevated voiding pressures in all but 1.7 Yeung et al studied 84 infants with reflux detected prenatally because of hydronephrosis and found increased bladder wall thickness in 24 of the boys. 8 These 2 studies suggest the possibility of transient bladder outflow obstruction with elevated intraluminal pressure, which might damage the kidneys during development; elevated intraluminal pressures are known to be able to produce renal scars indistinguishable from those caused by bacterial infection, especially in the young patient. 9· 10 It would be helpful to know to what extent these congenital renal changes account for the overall number of scars seen in association with reflux, and for this reason a good, noninvasive method to screen neonates for reflux and renal morphology would be of enormous value. Unfortunately, sonography will detect only reflux associated with dilatation of the collecting system and most other studies are invasive to some degree. A problem encountered in trying to resolve some of these issues is the difficulty in documenting the presence of a scar. Whether one uses the nephrogram from an excretory urogram, 11 a dimercaptosuccinic acid scan 4 or a 3-dimensional volume
AND
JAMES A. ROBERTS
scanner, 12 only relatively large scars can be seen and some of these become obvious only when growth of the surrounding normal parenchyma causes them to stand out in contrast. For this reason we may not be certain about scarring for several years until these changes become clearly defined. Smaller scars or subtle thinning of the renal parenchyma may represent injury beyond our ability to detect reliably with current techniques.13 However, the progressive decline in renal function noted by Berg following_pyelonephritis 14 a11d the_inexoI_able progression to renal failure in instances of advanced renal damage 15 remind us that no instance of renal injury should be taken lightly. Even some fundamental concepts regarding the etiology of reflux have gone through periods of revision. In early studies, many of which were based on static rather than voiding cystograms, it appeared that reflux in the human was categorically abnormal. Now it seems that a small percentage of otherwise normal infants may exhibit reflux, which usually resolves spontaneously within a few years. A similar phenomenon has been described in dogs 16 and in primates. 17 Another early concept about reflux was that it resulted from infravesical obstruction (bladder neck obstruction), which was consistent with the experimental production of reflux by banding the bladder neck. As this concept became discredited the pendulum swung to reflux as a primary ureterovesical anomaly. There is much evidence to support this philosophy; reflux may be identified prenatally by sonography, the incidence varies according to racial groups 18 and it shows a strong familial tendency indicative of a genetically transmitted disorder. 5 Yet the peak incidence in older children and the bimodal pattern of boys in infancy and girls later are not entirely consistent with a single etiology. 19 Current evidence favors a multifactorial origin for reflux: congenital in the infant and acquired, usually by voiding dysfunction, in the other child. An informed approach to the management of reflux requires a knowledge of its natural history. Thanks to the long-term studies of Smellie 20 and others 21 · 22 it is obvious that there is a tendency for reflux to resolve spontaneously with time but there is a decided difference in the rate of resolution depending upon the grade of reflux. The resolution rate of low grade reflux has been found to be as high as 85 % but this rate may be less than half of that for dilating reflux. 23 Across the board resolution of reflux averages about 50% in 5 years. Even when reflux persists, it usually declines in grade with time. Furthermore, there are fewer problems with recurrent urinary tract infections and fewer new scars appearing as the child grows older. There is concern about a recrudescense of pyelonephritis in women as they enter the sexually active and childbearing years but this too appears to have been overly stressed. Pyelonephritis of pregnancy does not correlate with reflux in the manner that might have been expected, and nowhere is there convincing evidence that correction of reflux by surgical intervention has any significant effect upon the incidence or severity of pyelonephritis of pregnancy. How, then, should reflux be treated? One indisputable point of agreement has been the importance of preventing secondary pyelonephritis. A major breakthrough in this regard has been the discovery that urinary tract infection and renal scars can generally be prevented by the use of continuous low dose prophylactic antibacterials. 23 Agents that are absorbed high in the gastrointestinal tract are best since they are the least likely to alter the colonic flora, the bacterial reservoir for future urinary tract infections. Nitrofurantoin and sulfamethoxazole-
1758
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VESICOURETERAL REFLUX-1992
trimethoprim preparations have been the most popular agents for this purpose but trimethoprim alone has proved satisfactory and may have fewer side effects. Prophylactic antibacterials not only seem to protect the urinary tract from the damage that pyelonephritis might cause but they also buy valuable time necessary to allow either the reflux to resolve spontaneously or the patient to reach an age when the clinical significance of the reflux is less. Another important concept that has surfaced has been that of prompt treatment whenever pyelonephritis develops. Several studies have shown that delay in the institution of treatment of pyelonephritis aggravates the resulting damage. 24 • 25 It is also apparent, although less clearly documented, that elevated intravesical pressure increases the extent of injury, so measures that might be undertaken to reduce these pressures should be encouraged. For dysfunctional voiding, which is a common condition in these patients, this may be as simple as initiating a program of bladder retraining. The role of ureteral reimplantation has not been as easy to define. There is general agreement that few indications exist for surgery in nondilating reflux. Secondary urinary tract infection in these patients is usually easily preventable by continuous antibacterial prophylaxis and the reflux generally resolves spontaneously anyway but there is less certainty about how to manage the higher grades of reflux. From the studies of Smellie20 and Bailey et al2 1 it is evident that long-term medical therapy is well tolerated and generally effective in preventing infection but reflux persists in many of these individuals and the threat of breakthrough infections, the risk of additional renal scarring and the need for supervision are psychologically debilitating for many patients. Surgical correction of reflux is successful in a high percentage of cases but complications do occur, and there is always the lingering suspicion that the patient might have fared as well without it. The International Reflux Study in Children was undertaken to resolve this dilemma by comparing outcomes in children with grades III and IV reflux randomized to medical or surgical treatment. This study has provided us with an enormous amount of information and some meaningful conclusions, although difficulties in making direct comparisons make some of the conclusions less than completely satisfying. For example, the incidence of urinary tract infection after initiation of treatment was the same in both groups but pyelonephritis occurred significantly less often in those treated surgically despite the fact that prophylactic antimicrobial agents were discontinued in the surgical group upon documentation that the reflux had been corrected successfully. 26 The incidence of new scars was also the same for both groups but those occurring in the surgical group generally appeared within 2 years after initiation of treatment, while those in the medical group continued to appear fairly evenly throughout followup. 27 The final conclusion of the study was that the outcome was similar whether medical or surgical therapy was selected but it would be of considerable interest to continue to follow these patients for an additional 5 years or more. Currently, it appears that the only absolute indication for surgical intervention remains failure of medical therapy but persistent reflux, breakthrough infections or simply the worry and expense of continued followup will probably drive many patients with higher grades of reflux to surgery before the debate is over. Superficially, the results of the attention and effort devoted to vesicoureteral reflux during the last 40 years might seem somewhat disappointing. It turns out that renal scars in patients with reflux may have been present from birth and, thus, not even preventable by current technology. Pyelonephritis is not always associated with reflux, nor does it always lead to scarring. Furthermore, correction of reflux may not necessarily prevent future infections. Both methods of treatment, medical and surgical, seem to work equally well. In fact, once reflux is identified and addressed appropriately it is unusual to see much
additional damage regardless of whether medical or surgical treatment is selected unless the kidney is heavily damaged at the outset, in which case a progressive decline in renal function can be expected regardless of how it is managed. In truth, the damage that occurs before reflux is recognized remains the single most important variable in the ultimate outcome of the disease process. A more positive view of the outcome of these labors is that they have directed our activities into ever more productive channels. They have convinced us, for example, that earlier recognition of reflux is essential for further therapeutic gains and sent us scurrying to find ways to screen for reflux at the beginning of life itself. They have also shown us that the enemy postnatally is pyelonephritis and perhaps elevated intraluminal pressures; vesicoureteral reflux is merely a vehicle, probably one of many, which facilitates the process. Finally, our findings have caused us to refocus our attention on the kidney, reminding us of the need for better understanding of the cellular events responsible for the parenchymal damage. International workshops in the future may discuss reflux only in passing while concentrating on such matters as bacterial virulence factors, host defense mechanisms, control of free oxygen radicals and even genetic engineering. We might summarize by saying that it is important to recognize reflux early, establish an effective therapeutic program promptly and follow the patient conscientiously. In most cases this will entail an initial program of prophylactic antibacterials and attention to factors, anatomical or functional, that lead to elevated intraluminal pressures or residual urine. For low grade reflux this is likely to be all that is required. For higher grades of persistent reflux consideration should be given to ureteral reimplantation as a legitimate alternative to long-term medical treatment. REFERENCES
1. Hutch, J. A.: Vesicoureteral reflux in the paraplegic: cause and correction. J. Urol., 68: 457, 1952. 2. Hodson, C. J. and Edwards, D.: Chronic pyelonephritis and vesicoureteric reflux. Clin. Rad., 11: 219, 1960. 3. Roberts, J. A.: Etiology and pathophysiology of pyelonephritis. Amer. J. Kidney Dis., 17: 1, 1991. 4. Rushton, H. G. and Majd, M.: Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J. Urol., part 2, 148: 1726, 1992. 5. Noe, H. N.: The long-term results of prospective sibling reflux screening. J. Urol., part 2, 148: 1739, 1992. 6. Winberg, J., Bollgren, I., Kallenius, G., Mollby, R. and Svenson, S. B.: Clinical pyelonephritis and focal renal scarring. A selected review of pathogenesis, prevention, and prognosis. Ped. Clin. N. Amer., 29: 801, 1982. 7. Sillen, U., Hjii.lmas, K., Aili, M., Bjure, J., Hanson, E. and Hansson, S.: Pronounced detrusor hypercontractility in infants with gross bilateral reflux. J. Urol., part 2, 148: 598, 1992. 8. Yeung, C. K., Dhillon, H. K., Duffy, P. G. and Ransley, P. G.: Vesicoureteric reflux in infants with prenatally diagnosed hydronephrosis. Read at annual meeting of Section on Urology, American Academy of Pediatrics, New Orleans, Louisiana, October 28, 1991. 9. Hodson, C. J., Maling, T. M. J., McManamon, P. J. and Lewis, M. G.: The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Brit. J. Rad., suppl., 13: 1, 1975. 10. Mendoza, J.M. and Roberts, J. A.: Effects of sterile high pressure vesicoureteral reflux on the monkey. J. Urol., 130: 602, 1983. 11. Smellie, J., Edwards, D., Hunter, N., Normand, I. C. S. and Prescod, N.: Vesico-ureteric reflux and renal scarring. Kidney Int., 8: 65, 1975. 12. Joseph, D. B., Young, D. W. and Jordan, S. P.: Renal cortical scintigraphy and single proton emission computerized tomography (SPECT) in the assessment of renal defects in children. J. Urol., part 2, 144: 595, 1990. 13. Bernstein, J. and Arant, B. S., Jr.: Morphological characteristics of segmental renal scarring in vesicoureteral reflux. J. Urol., part 2, 148: 1712, 1992.
1760
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14. Berg, U. B.: Long-term followup of renal morphology and function in children with recurrent pyelonephritis. J. Urol., part 2, 148: 1715, 1992. 15. Jacobson, S. H., Eklof, 0. and Eriksson, C. G.: Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. Brit. Med. J., 299: 703, 1989. 16. Christie, B. A.: Incidence and etiology of vesicoureteral reflux in apparently normal dogs. Invest. Urol., 9: 184, 1971. 17. Roberts, J. A. and Riopelle, A. J.: Vesicoureteral reflux in the primate. II. Maturation of the ureterovesical junction. Pediatrics, 59: 566, 1977. 18. Askari, A. and Belman, A. B.: Vesicoureteral reflux in black girls. J. Urol., 127: 747, 1982. 19. King, L. R.: Vesicoureteral reflux: history, etiology and conservative management. In: Clinical Pediatric Urology. Edited by P. P. Kelalis and L. R. King. Philadelphia: W. B. Saunders Co., chapt. 11,pp. 342-365, 1976. 26. Smellie;--·J. !v1::--Reflections on -30-years-of treating childr-en \vith urinary tract infections. J. Urol., part 2, 146: 665, 1991. 21. Bailey, R. R., Lynn, K. L. and Smith, A. H.: Long-term followup of infants with gross vesicoureteral reflux. J. Urol., part 2, 148: 1709, 1992.
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