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Familial Vesicoureteral Reflux
Vol. 108, December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1972 by The Williams & Wilkins Co.
FAMILIAL VESICOURETERAL REFLUX AlUAN D. AMAR Frcrn the Deparlrnent of Urology, The Permanente Medical Grollp, Kaiser Follnclation Hospital, Walnllt Creek ancl the Division of Urology, University of California, San Francisco, California
Bacteria that reach the kidney through vesicoureteral reflux may cause or perpetuate pyelonephritis. Reflux may exist without pyelonephritis especially in male subjects. Once bacteria are introduced into the bladder with reflux they can reach the kidney and may damage or destroy it before warning symptoms arise. Thus, any clue leading to the early detection of reflux is important. Reflux has been noted to be familial in at least some instances. 1 - 3 Among 320 consecutive cases of reflux that I have seen in the last 10 years, 19 cases were familial (fig. 1). In most of these cases reflux was discovered while the patient was being studied because of symptoms. However, in several more recent cases awareness that reflux may be familial led to a search for the abnormality in close relatives. Herein I present some experiences in detecting familial reflux.
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CASE REPOR'rs
Family 1. A 3-year-old girl was observed for 2 years after detection of bilateral vesicoureteral reflux (fig. 2, A). Recurrent acute pyelonephritis then necessitated bilateral ureteral reimplantation. Postoperatively, the child's mother mentioned that her 23,f-year-old daughter was having symptoms like those experienced by the propositus 2 years earlier. The younger child was found to have bilateral reflux and is being followed closely (fig. 2, B). The mother was having recurrent cystitis and was found to have unilateral reflux (fig. 2, C). She recalled having had unexplained fever from age 3 to 8 years. The reflux was corrected surgically. Family 2. Bilateral vesicoureteral reflux was found in a 12-year-old girl with recurrent urinary tract infection. A few months later her 7-year-old sister was referred for investigation of high fever and urinary tract infection; bilateral reflux was found. On questioning, it was learned that a 4-yearold sister had been treated for urinary tract infection but had not been investigated for reflux. Although she had no infection or symptoms at that time,
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* Duplicoled urinary system
Fm. 1. Eight families having more than 1 member with vesicoureteral reflux. voiding cystograms showed bilateral reflux. Because reflux had been found in the 3 sisters, we studied their 3 brothers, aged 10, 14 and 17 years, all of whom were free of symptoms. Bilateral reflux was found in the IO-year-old boy, who had no history of urinary tract infection and in whom excretory urography and renal function studies were relatively normal. He was observed for 2 years and increasing hydronephrosis was seen. He and 2 sisters have required surgical correction of reflux while the third sister is being followed closely. Urologic studies of both parents revealed no evidence of reflux. Family 3. Two years left ureteral with reflux into both the duplicate ureters was found in a 4-year-old girl with acute left phritis (fig. 3, A). The reflux was and the child has remained well. for 8}3y1nptorn.atic sister,
Accepted for publication June 2, 1972. Requests for reprints: 1515 Newell Avenue, Walnut Creek, California 94596. 1 Stephens, F. D., Joske, R. A. and Simmons, R. T.: Megaureter with vesico-ureteric reflux in twins. Aust. New Zeal. J. Surg., 24: 192, 1955. 2 Tobenkin, M. I.: Hereditary vesicoureteral reflux. Southern Med. J., ,57: 139, 1964. 3 Mulcahy, J. J., Kelalis, P. P., Stickler, G. B. and Burke, E. C.: Familial vesicoureteral reflux. J. Ural., Hl4: 762, 1970.
969
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970
AMAR
FIG. 2. A, bilateral vesicoureteral reflux in 3-year-old girl. B, bilateral reflux seen 2 years later in her 2½year-old sister. C, unilateral reflux in mother of these 2 girls.
FIG. 3. A, duplicate left ureter with reflux into both branches in 4-year-old girl with acute left pyelonephritis. B, left ureteral duplication with reflux into both duplicated ureters and into opposite single ureter in her 2-year-old sister. bacilluria, was discovered to have left ureteral duplication with reflux into both duplicated ureters and into the opposite single ureter (fig. 3, B). Surgical correction of the reflux is planned. DISCUSSION
The urinary tract anomalies with which reflux is often associated are frequently familial. Several investigators have noted that reflux occurs more
often in duplicated than in single ureters, 4- 8 and 4 Ambrose, S. S. and Nicolson, W. P.: Ureteral reflux in duplicated ureters. J. Urol., 92: 439, 1964. 5 Amar, A. D.: Reflux in duplicated ureters. Brit. J. Urol., 40: 385, 1968. 6 Thompson, I. M. and Amar, A. D.: Clinical importance of ureter al duplication and ectopia. J.A.M.A., 168: 881, 1958. 7 Amar, A. D. and Hutch, J. A.: Anomalies of the ureter. In: Encyclopedia of Urology. Edited by C. E. Alken, V. W. Dix, W. E. Goodwin, H. M. Weyrauch
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971
FAMILIAL VESICOURETERAL REFLUX
Whitaker and Danks 9 found unsuspected duplication of the urinary tract in 16 of 126 relatives of 39 patients with duplication. In 3 of the 8 families reported herein, ureteral duplication and reflux were combined: 2 sisters in each of 2 families and a mother and daughter in another family had duplication and reflux (fig. 1). The frequency with ,vhich reflux is familial cannot be assessed until familial instances are actively sought. A number of factors make it difficult to investigate families for this abnormality. The pediatrician who treats a child with reflux may never see the siblings because the family has moved elsewhere. The physician treating a patient of any age may never see the close relatives because lines of medical specialization are not crossed. Investigation may appear forbidding to the asymptomatic person whose physician must state that the probability of familial involvement is not certain. The families reported herein were easily persuaded to have themselves evaluated. They reside in a community of relatively high educational level and social stability and are members of a prepaid health plan that covers diagnosis and treatment. Symptomatic relatives were referred to the medical group's department of urology by physicians in a variety of other specialties, leading to the recognition of familial reflux in cases that might have gone unnoticed if referrals had been more diffuse. The benefits to be gained outweigh the obstacles to early detection. Some children outgrow reflux as the vesicoureteral junction matures from infancy to and E. Wildbolz. New York: Springer-Verlag, vol. VII, pp. 98-164, 1968. 8 Amar, A. D. and Chabra, K.: Reflux in duplicated ureters: treatment in children. J. Pediat. Surg., 5: 419, 1970. 9 Whitaker, J. and Danks, D. M.: A study of the inheritance of duplication of the kidneys and ureters. J. Urol., 95: 176, 1966.
puberty but there is no known basis for predicting this in the individual case. Asymptomatic reflux has the same potential for renal destruction as symptomatic reflux and may demand as much treatment. We have seen patients whose kidneys were destroyed Ly asymptomatic pyelonephritis, with or without associated ureteral dilatation. Modern surgical procedures have cured reflux in 95 to 98 per cent of patients in major series. 4 Many patients are managed medically throughout their course and some are managed medically for years before operation becomes necessary. However, some patients require early surgical treatment because of renal damage present when reflux is detected or because in the given situation medical treatment can be expected to fail. Reflux requires close followup until there is convincing evidence that it has ceased with medical treatment or has not recurred after surgical correction. After reflux is cured, interval observation for recurrence of pyelonephritis is recommended. Any person who has a close relative with known reflux should be investigated for reflux if he or she has a history of symptoms pertaining to urinary tract infection, voiding abnormalities, decreased renal function or dilatation of the upper urinary tract without obvious cause. SUMMARY
The knowledge that vesicoureteral reflux can be familial offers an important clue to its early detection. Since part or all of a kidney may be destroyed by silent pyelonephritis resulting from unrecognized reflux, close relatives of patients known to have reflux should be studied despite lack of symptoms. If reflux is found, treatment to forestall or arrest pyelonephritis must be given as for symptomatic disease. Lengthy followup is suggested in order to detect recurrence.
THE JOURNAL OF UROLOGY
Copyright © 1972 by The Williams & Wilkins Co.
FAMILIAL VESICOURETERAL REFLUX AlUAN D. AMAR Frcrn the Deparlrnent of Urology, The Permanente Medical Grollp, Kaiser Follnclation Hospital, Walnllt Creek ancl the Division of Urology, University of California, San Francisco, California
Bacteria that reach the kidney through vesicoureteral reflux may cause or perpetuate pyelonephritis. Reflux may exist without pyelonephritis especially in male subjects. Once bacteria are introduced into the bladder with reflux they can reach the kidney and may damage or destroy it before warning symptoms arise. Thus, any clue leading to the early detection of reflux is important. Reflux has been noted to be familial in at least some instances. 1 - 3 Among 320 consecutive cases of reflux that I have seen in the last 10 years, 19 cases were familial (fig. 1). In most of these cases reflux was discovered while the patient was being studied because of symptoms. However, in several more recent cases awareness that reflux may be familial led to a search for the abnormality in close relatives. Herein I present some experiences in detecting familial reflux.
•
CASE REPOR'rs
Family 1. A 3-year-old girl was observed for 2 years after detection of bilateral vesicoureteral reflux (fig. 2, A). Recurrent acute pyelonephritis then necessitated bilateral ureteral reimplantation. Postoperatively, the child's mother mentioned that her 23,f-year-old daughter was having symptoms like those experienced by the propositus 2 years earlier. The younger child was found to have bilateral reflux and is being followed closely (fig. 2, B). The mother was having recurrent cystitis and was found to have unilateral reflux (fig. 2, C). She recalled having had unexplained fever from age 3 to 8 years. The reflux was corrected surgically. Family 2. Bilateral vesicoureteral reflux was found in a 12-year-old girl with recurrent urinary tract infection. A few months later her 7-year-old sister was referred for investigation of high fever and urinary tract infection; bilateral reflux was found. On questioning, it was learned that a 4-yearold sister had been treated for urinary tract infection but had not been investigated for reflux. Although she had no infection or symptoms at that time,
*
' '
*
' '
* Duplicoled urinary system
Fm. 1. Eight families having more than 1 member with vesicoureteral reflux. voiding cystograms showed bilateral reflux. Because reflux had been found in the 3 sisters, we studied their 3 brothers, aged 10, 14 and 17 years, all of whom were free of symptoms. Bilateral reflux was found in the IO-year-old boy, who had no history of urinary tract infection and in whom excretory urography and renal function studies were relatively normal. He was observed for 2 years and increasing hydronephrosis was seen. He and 2 sisters have required surgical correction of reflux while the third sister is being followed closely. Urologic studies of both parents revealed no evidence of reflux. Family 3. Two years left ureteral with reflux into both the duplicate ureters was found in a 4-year-old girl with acute left phritis (fig. 3, A). The reflux was and the child has remained well. for 8}3y1nptorn.atic sister,
Accepted for publication June 2, 1972. Requests for reprints: 1515 Newell Avenue, Walnut Creek, California 94596. 1 Stephens, F. D., Joske, R. A. and Simmons, R. T.: Megaureter with vesico-ureteric reflux in twins. Aust. New Zeal. J. Surg., 24: 192, 1955. 2 Tobenkin, M. I.: Hereditary vesicoureteral reflux. Southern Med. J., ,57: 139, 1964. 3 Mulcahy, J. J., Kelalis, P. P., Stickler, G. B. and Burke, E. C.: Familial vesicoureteral reflux. J. Ural., Hl4: 762, 1970.
969
-~~-~----------~-
970
AMAR
FIG. 2. A, bilateral vesicoureteral reflux in 3-year-old girl. B, bilateral reflux seen 2 years later in her 2½year-old sister. C, unilateral reflux in mother of these 2 girls.
FIG. 3. A, duplicate left ureter with reflux into both branches in 4-year-old girl with acute left pyelonephritis. B, left ureteral duplication with reflux into both duplicated ureters and into opposite single ureter in her 2-year-old sister. bacilluria, was discovered to have left ureteral duplication with reflux into both duplicated ureters and into the opposite single ureter (fig. 3, B). Surgical correction of the reflux is planned. DISCUSSION
The urinary tract anomalies with which reflux is often associated are frequently familial. Several investigators have noted that reflux occurs more
often in duplicated than in single ureters, 4- 8 and 4 Ambrose, S. S. and Nicolson, W. P.: Ureteral reflux in duplicated ureters. J. Urol., 92: 439, 1964. 5 Amar, A. D.: Reflux in duplicated ureters. Brit. J. Urol., 40: 385, 1968. 6 Thompson, I. M. and Amar, A. D.: Clinical importance of ureter al duplication and ectopia. J.A.M.A., 168: 881, 1958. 7 Amar, A. D. and Hutch, J. A.: Anomalies of the ureter. In: Encyclopedia of Urology. Edited by C. E. Alken, V. W. Dix, W. E. Goodwin, H. M. Weyrauch
-J
971
FAMILIAL VESICOURETERAL REFLUX
Whitaker and Danks 9 found unsuspected duplication of the urinary tract in 16 of 126 relatives of 39 patients with duplication. In 3 of the 8 families reported herein, ureteral duplication and reflux were combined: 2 sisters in each of 2 families and a mother and daughter in another family had duplication and reflux (fig. 1). The frequency with ,vhich reflux is familial cannot be assessed until familial instances are actively sought. A number of factors make it difficult to investigate families for this abnormality. The pediatrician who treats a child with reflux may never see the siblings because the family has moved elsewhere. The physician treating a patient of any age may never see the close relatives because lines of medical specialization are not crossed. Investigation may appear forbidding to the asymptomatic person whose physician must state that the probability of familial involvement is not certain. The families reported herein were easily persuaded to have themselves evaluated. They reside in a community of relatively high educational level and social stability and are members of a prepaid health plan that covers diagnosis and treatment. Symptomatic relatives were referred to the medical group's department of urology by physicians in a variety of other specialties, leading to the recognition of familial reflux in cases that might have gone unnoticed if referrals had been more diffuse. The benefits to be gained outweigh the obstacles to early detection. Some children outgrow reflux as the vesicoureteral junction matures from infancy to and E. Wildbolz. New York: Springer-Verlag, vol. VII, pp. 98-164, 1968. 8 Amar, A. D. and Chabra, K.: Reflux in duplicated ureters: treatment in children. J. Pediat. Surg., 5: 419, 1970. 9 Whitaker, J. and Danks, D. M.: A study of the inheritance of duplication of the kidneys and ureters. J. Urol., 95: 176, 1966.
puberty but there is no known basis for predicting this in the individual case. Asymptomatic reflux has the same potential for renal destruction as symptomatic reflux and may demand as much treatment. We have seen patients whose kidneys were destroyed Ly asymptomatic pyelonephritis, with or without associated ureteral dilatation. Modern surgical procedures have cured reflux in 95 to 98 per cent of patients in major series. 4 Many patients are managed medically throughout their course and some are managed medically for years before operation becomes necessary. However, some patients require early surgical treatment because of renal damage present when reflux is detected or because in the given situation medical treatment can be expected to fail. Reflux requires close followup until there is convincing evidence that it has ceased with medical treatment or has not recurred after surgical correction. After reflux is cured, interval observation for recurrence of pyelonephritis is recommended. Any person who has a close relative with known reflux should be investigated for reflux if he or she has a history of symptoms pertaining to urinary tract infection, voiding abnormalities, decreased renal function or dilatation of the upper urinary tract without obvious cause. SUMMARY
The knowledge that vesicoureteral reflux can be familial offers an important clue to its early detection. Since part or all of a kidney may be destroyed by silent pyelonephritis resulting from unrecognized reflux, close relatives of patients known to have reflux should be studied despite lack of symptoms. If reflux is found, treatment to forestall or arrest pyelonephritis must be given as for symptomatic disease. Lengthy followup is suggested in order to detect recurrence.