Vol. 115, June
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
Printed in U.S.A.
THE NATURAL HISTORY OF REFLUX AND LONG-TERM EFFECTS OF REFLUX ON THE KIDNEY DANIEL LENAGHAN,* JOHN G. WHITAKER, FREDERICK JENSENt
AND
F. DOUGLAS STEPHENS:j:
From the Royal Children's Hospital Research Foundation, Melbourne, Australia
ABSTRACT
Spontaneous cessation of vesicoureteral reflux occurred in 42 per cent of 102 patients. It ceased in 65 per cent of the patients with unilateral reflux, in 50 per cent of those with bilateral reflux in normal caliber ureters and in 9 per cent of those with bilateral dilated ureters. Renal parenchymal changes were seen most frequently in patients with urinary infection after diagnosis. The likelihood of such infections lessened if reflux ceased. Proportionately more male than female subjects were free of infection. Renal damage may follow even 1 episode of infection. Lesions appeared with equal frequency during the entire followup period, whereas urinary infection was more common in the 5-year period after diagnosis. Renal damage was more likely to occur in kidneys that were already abnormal. Reflux should be controlled surgically if urinary infections occur after diagnosis and during long-term chemotherapy and careful observation. In the absence of infection indications for operation are infrequent. Non-surgical management may apply to normal caliber ureters and in infancy, while antireflux operation may be considered at diagnosis in dilated ureters, bilateral reflux or in the presence of renal lesions. The present management of primary vesicoureteral reflux requires the appropriate selection of surgical or non-surgical treatment in individual patients. There is no universal agreement regarding the criteria used in making this choice. A series of 102 patients with reflux alone treated without an antireflux operation has been studied. The results presented herein have enabled recognition of certain clinical situations and their sequela which, in tum, allows for an earlier decision regarding the most appropriate treatment. A preliminary report was made in 1970. 1
old, 35 were 15 to 19 years old and 11 were 20 to 29 years old. Followup ranged from 5 to 9 years in 65 patients, 10 to 14 years in 25 and 15 to 18 years in 12. RESULTS
MATERIAL AND METHODS
The 102 patients with reflux alone were managed on a regimen of multiple micturition, intermittent chemotherapy and some ablative operation for 5 to 18 years. An additional 19 patients with inadequate followup and those in whom reflux was associated with ureteral duplications, vesical diverticula, urethral valves, neurogenic bladder or iatrogenic causes were excluded from the study. The patients included 35 boys and 67 girls. Reflux was bilateral in 30 (80 per cent) boys and 37 (55 per cent) girls, making a total of 167 ureters. The boys were referred mainly during the first year of life and 80 per cent of them were seen by the age of 3 years. The maximum incidence in girls occurred at the age of 7 years, with only a quarter of them having been seen by the age of 3 years (see figure). Urinary tract infections were present in 25 (71 per cent) boys and 62 (93 per cent) girls. Information was tabulated from the clinical history and results of previous urinalyses, excretory urograms (IVPs) and micturition cystourethrograms. All patients were assessed finally by blood pressure and blood urea estimations, microscopy and urine cultures, IVP and, if reflux was present on the preceding occasion, micturition cystourethrograms. At final followup 19 patients were 5 to 9 years old, 37 were 10 to 14 years Accepted for publication October 10, 1975. * Current address: Urological Clinic, St. Vincent's Hospital, Melbourne, Australia. t Current address: Department of Radiology, Royal Children's Hospital, Melbourne, Australia. :j:Requests for reprints: Department of Surgery, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614.
Natural cessation of reflux. Of 167 ureters 83 displayed natural cessation of reflux. Factors influencing cessation were the caliber of the ureter and the age of the patient at the time of diagnosis. Reflux ceased in 65 (66 per cent) of98 normal caliber ureters, that is those measuring up to 1.0 cm. maximum width on micturition cystourethrography. Cessation occurred in 15 (33 per cent) of 48 moderately dilated ureters (LO to 2.0 cm. maximum width on micturition cystourethrography) and in only 3 (14 per cent) of 21 grossly dilated ureters (more than 2.0 cm. maximum width on micturition cystourethrography). Thus, of 69 dilated ureters 18 (26 per cent) ceased to reflux. Ureteral dilatation often diminished despite persistent reflux. Of the dilated ureters 15 (22 per cent) retained reflux but reverted to normal caliber and 36 (52 per cent) retained reflux and dilatation at the end of followup. Of 21 ureters initially grossly dilated 5 became moderately dilated and 1 reached normal caliber wi:th persistent reflux. Of 33 normal caliber ureters with persistent reflux only 2 were dilated, both in a girl with an occult neurogenic bladder disturbance discovered later on cystography. Over-all, 43 (42 per cent) of the patients were free of reflux. Unilateral reflux ceased in 24 (65 per cent) of 37 patients. Of 31 patients with bilateral reflux in normal caliber ureters 16 (50 per cent) became free of reflux but in only 3 (9 per cent) of 34 patients with bilateral dilated ureters did reflux cease. Age and cessation of reflux: The younger the patient at the time of presentation the greater the likelihood of early cessation of reflux. Of 22 ureters in patients seen during the first year of life reflux ceased in 15 (68 per cent) by the time the patient was 14 years old. In 7 of these ureters reflux ceased before the patient was 6 years old and in 13 by the time the patient was 9 years old. Of 18 ureters in patients between 1 and 2 years of age 8 (44 per cent) ceased to reflux by the time the patient was 14 years old. Reflux ceased in 2 of these 8 ureters before the patient was 6 years old. Of 19 ureters in patients between 2 and 3 years of age none lost reflux before
728
lil
N!JMBS:f.! of PATlENTS
0
6
10 YEI.J~S OF AGE
Graph shows age of patients at time of diagnosis of reflux and maximum incidence in boys during first year of life and in girls at 7 years of age.
the patient was 6 years oid and only 7 (37 per cent) ceased to reflux by the time the patient was 14 years old. Of 117 ureters in patients between 3 and 12 years of age 31 (26 per cent) ceased to have reflux by the time the patient was 14 years old. Of the total 83 ureters in which reflux ceased 22 (27 per cent) did so after the was 14 years old. on renal parenchyma. In 120 of the 167 refluxing ureters adequate to cornpare the renal parenchyma at the time of diagnosis and were available. The criteria of Hodson and associates were used to assess renal length. 2 Tracings of the renal outlines and inlines (pelviocaliceal systems) were made to detect renal scarring, focal and general thinning, and caliceal clubbing. Of 76 kidneys considered normal at 16 (21 per cent) in 13 patients showed deterioration during Of 44 recognized as abnormal at the time of diagnosis 29 (66 per cent) underwent further deterioration. Of the 45 that deteriorated 27 ,,vere associated with persistent reflux and ureteral reflux ceased in 18. Deterioration was seen in with either normal caliber or dilated ureters. the 16 kidneys that were normal revealed that the ureters were dilated in 13 ( 4 and 9 . All of these patients were seen before were 7 years old and 9 of them before the of 3 years. Reflux was bilateral in 11 of the 13 patients was present for 3 years in l and from 6 to 13 years i.,, 12. Twelve of the 13 had documented verse features of infection and dilated ureters. There were num_erous instances of reflux. Two presence of 1 after contralateral ,,,..,p,.,1·,nnv and 1 vvith bilateral reflux. There were 6 with absence of and 3 with all of which had persistent ureteral reflux. One vesicoureteral reflux had ceased also There were 12 patients with elevated blood urea levels at the end of followup but 10 of them had had elevated levels at the time of diagnosis. All children had bilateral reflux except 1 who had unilateral reflux and hypertension. Hypertension (more than 140 mm. Hg systolic or 90 mm. Hg diastolic) developed in 10 patients. Of these 10 children 3 had elevated blood urea levels, 3 had urinary infection at final followup and 3 of the 4 kidneys undergoing contraction were in hypertensive patients. Reflux and urinary infection. Infection was diagnosed by the growth of a single strain of organism in significant numbers from a midstream or catheter specimen of urine. After diagnosis 20 boys and 20 girls had no further documented infections.
2.6
in 42 3.7 There were 6 patients with incomplete At the end of 2 and 10 girls all of whom exhibited reflux. Infection was mainly associated with persistent reflux. No episodes of infection occurred in in whom reflux ceased but there were 12 of 29 girls (41 per cent) who had further infection after reflux ceased. Urinary infection and renal damage: Renal damage was more likely in patients with proved infection. In 25 of the 56 patients in whom infection was diagnosed lesions developed in 35 kidneys, 7 in 5 and 28 in 20 girls. In 7 of the 40 patients free of further infection 10 kidneys underwent deterioration, 5 in 4 boys and 5 in 3 girls. Renal damage was just as likely in patients with 1 infection episode as in those with numerous episodes. For example, 18 renal lesions developed in 20 patients who had 1 episode of infection, while 6 lesions occurred in 9 patients who had 6 or more episodes. Although renal lesions appeared during the entire followup period, proved episodes of infection in the presence of reflux were more common during the first 5 years after diagnosis. After this time less than half of the patients followed had infection. DISCUSSION
Factors in renal damage. The incidence of renal damage at the time of diagnosis in children with reflux is high. 120 kidneys with reflux in our series 44 (36 per cent) were abnom1al at diagnosis. In other series 54 per cent of the kidneys 3 and 15 to 35 per cent of the patients with reflux had scarring. H Lesions in 21 per cent of initially normal kidneys and in 66 per cent of those initially abnormal, compared to 12.5 and 62.5 per cent, respectively, reported elsewhere. 7 Renal damage in normal kidneys was seen usually in those patients with dilated ureters but deterioration in initially abnormal kidneys occurred irrespective of ureteral caliber. 8 Renal lesions were more numerous when infection was recorded and the latter was more common in the presence of reflux. The appearance of renal lesions at the same rate throughout the years of suggested that the longer reflux the more likely renal damage was to occur. The development of lesions in normal kidneys to reflux and infection indicated that antireflux operation should improve their outlook. Absence of further deterioration after an antireflux operation 3• 6 has been observed in these those patients in whom reflux will cease within a short time after dilatation or internal has been required in 20 to 60 per non-cessation of reflux as the sole criterion operation 58 per cent of our would If recurrence of infection were the indication the same number of (60 per cent) The
ureter ceasing to guide upon which to determine an ""Qrrwr·n appearance of the ureteraI orifice 11 can be useful in this decision. Excluding those orifices in which reflux is most likely to cease an operation appears indicated if infection occurs after diagnosis. An exception may be made in babies in whom the kidney and ureteral caliber are near normal. 8 Reflux and infection. Although sterile reflux has been reported to cause renal damage 12 or even end stage renal failure, 13 other experimental and clinical evidence has shown it can be harmless. 10 • 14 ' 15 In our series infection in patients with reflux was more common during the first 5 years after diagnosis whereas renal iesion appeared throughout followup. The failure to note infection in long-standing reflux and the long time ~o,,v-,v~
730
LENAGHAN AND ASSOCIATES
taken for radiologic evidence of damage to appear after infection 7 suggest that some examples of renal damage in apparently sterile reflux may have an infective basis. Occurrence of urinary infections is recognized after the cessation or control of reflux and incidences from 20 to 58 per cent have been recorded. 1 •· 18 In our series no infections occurred after cessation in boys but it was noted in 41 per cent of the girls. Reflux was more common in boys during infancy and in girls during childhood. A similar relation has been noted for clinical and asymptomatic urinary infections, which has led to the consideration that infection may cause reflux. 19 Descriptions of the pathology of the intravesical portion of the ureter permitting reflux indicate a muscular defect without evidence of damage caused by chronic infection. 20 • 21 Experimental and clinical observations have shown that acute cystitis may cause reflux. 22 • 23 However, this must be a rare cause in children with reflux when the urine is sterile, often on more than 1 occasion, and accompanied by cystoscopic abnormalities of the ureteral orifices. Reflux and infection appear to have no etiologic relation in children but renal damage requires their simultaneous presence. ADDENDUM
These studies record the results of non-operative management of vesicoureteral reflux during a 20-year span when present day drugs were not so readily available and regimens of chemotherapy were experimental and emerging. With the introduction of low dose prophylactic therapy as now prescribed, recurrent infections and renal scarring may have been considerably reduced. These factors should be considered when drawing conclusions from the facts recorded herein.
8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20. 21.
REFERENCES
1. Stephens, F. D.: Preliminary followup study of 101 children with reflux treated conservatively. In: Renal Infection and Renal Scarring, 2nd ed. Edited by P. K. Smith and K. F. Fairley. Australia: Melbourne Mercedes Publishing Services, p. 283, 1970. 2. Hodson, C. J., Drewe, J. A., Karn, M. N. and King, A.: Renal size in normal children. A radiographic study during life. Arch. Dis. Child., 37: 616, 1962. 3. Hutch, J. A., Smith, D.R. and Osborne, R.: Review of a series of ureterovesicoplasties. J. Urol., 100: 285, 1968. 4. Brannan, W., Ochsner, M. G., Rosencrantz, D. R., Whitehead, C. M., Jr. and Goodier, E. H.: Experiences with vesicoureteral reflux. J. Urol., 109: 46, 1973. 5. Williams, D. I. and Eckstein, H.B.: Surgical treatment of reflux in children. Brit. J. Urol., 37: 13, 1965. 6. Dwoskin, J. Y. and Perlmutter, A. D.: Vesicoureteral reflux in children: a computerized review. J. Urol., 109: 888, 1973. 7. Filly, R., Friedland, G. W., Govan, D. E. and Fair, W. R.:
22. 23.
Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology, 113: 145, 1974. Rolleston, G. L., Shannon, F. T. and Utley, W. L.: Relationship of infantile vesicoureteric reflux to renal damage. Brit. Med. J., 1: 460, 1970. Allison, R. C. and Leadbetter, G. W., Jr.: The effect ofurethrotomy on vesicoureteral reflux. J. Urol., 108: 480, 1972. King, L. R., Surian, M. A., Wendel, R. M. and Burden, J. J.: Vesicoureteral reflux: a classification based on cause and the results of treatment. J.A.M.A., 203: 169, 1968. Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969. Hutch, J. A. and Smith, D. R.: Sterile reflux: report of 24 cases. Urol. Int., 24: 460, 1969. Salvatierra, 0., Jr., Kountz, S. L. and Belzer, F. 0.: Primary vesicoureteral reflux and end-stage renal disease. J.A.M.A., 226: 1454, 1973. Lenaghan, D., Cass, A. S., Cussen, L. J. and Stephens, F. D.: Long-term effect of vesicoureteral reflux on the upper urinary tract of dogs: I. Without urinary infection. J. Urol., 107: 755, 1972. Thompson, I. M., Karow, W. F. and Ross, G., Jr.: Long-term results of ureteral reimplantation for trauma. J. Urol., 102: 308, 1969. Kendall, A. R. and Karafin, L.: Urinary tract infection in children: fact and fantasy. J. Urol., 107: 1068, 1972. Amar, A. D. and Singer, B.: Vesicoureteral reflux: a 10-year study of 280 patients. J. Urol., 109: 999, 1973. Govan, D. E. and Palmer, J. M.: Urinary tract infection in children. The influence of successful antireflux operations in morbidity from infection. Pediatrics, 44: 677, 1969. Stamey, T. A.: Urinary Infections. Baltimore: The Williams & Wilkins Co., chapt. 5, 1972. Stephens, F. D. and Lenaghan, D.: The anatomical basis and dynamics of vesicoureteral reflux. J. Urol., 87: 669, 1962. Tanagho, E. A., Guthrie, T. H. and Lyon, R. P.: The intravesical ureter in primary reflux. J. Urol., 101: 824, 1969. Auer, J. and Seager, L. D.: Experimental local bladder edema causing urine reflux into ureters and kidneys. Proc. Soc. Exp. Biol. Med., 35: 361, 1936. · Hanley, H. G.: Pyelonephritis and lower urinary-tract inflammation. Lancet, 1: 22, 1963. COMMENT
The urological surgeon should have these facts clearly in mind when recommending treatment for the patient with reflux. Modern chemotherapy and antibiotic treatment should improve the results by lessening the recurrence of infection and the incidence of renal damage. Certainly all patients with low grades of reflux who have no renal damage deserve a period of observation on a good chemotherapeutic regimen before considering surgical correction of reflux.
Robert D. Jeffs The Johns Hopkins Hospital Baltimore, Maryland
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
Printed in U.S.A.
THE NATURAL HISTORY OF REFLUX AND LONG-TERM EFFECTS OF REFLUX ON THE KIDNEY DANIEL LENAGHAN,* JOHN G. WHITAKER, FREDERICK JENSENt
AND
F. DOUGLAS STEPHENS:j:
From the Royal Children's Hospital Research Foundation, Melbourne, Australia
ABSTRACT
Spontaneous cessation of vesicoureteral reflux occurred in 42 per cent of 102 patients. It ceased in 65 per cent of the patients with unilateral reflux, in 50 per cent of those with bilateral reflux in normal caliber ureters and in 9 per cent of those with bilateral dilated ureters. Renal parenchymal changes were seen most frequently in patients with urinary infection after diagnosis. The likelihood of such infections lessened if reflux ceased. Proportionately more male than female subjects were free of infection. Renal damage may follow even 1 episode of infection. Lesions appeared with equal frequency during the entire followup period, whereas urinary infection was more common in the 5-year period after diagnosis. Renal damage was more likely to occur in kidneys that were already abnormal. Reflux should be controlled surgically if urinary infections occur after diagnosis and during long-term chemotherapy and careful observation. In the absence of infection indications for operation are infrequent. Non-surgical management may apply to normal caliber ureters and in infancy, while antireflux operation may be considered at diagnosis in dilated ureters, bilateral reflux or in the presence of renal lesions. The present management of primary vesicoureteral reflux requires the appropriate selection of surgical or non-surgical treatment in individual patients. There is no universal agreement regarding the criteria used in making this choice. A series of 102 patients with reflux alone treated without an antireflux operation has been studied. The results presented herein have enabled recognition of certain clinical situations and their sequela which, in tum, allows for an earlier decision regarding the most appropriate treatment. A preliminary report was made in 1970. 1
old, 35 were 15 to 19 years old and 11 were 20 to 29 years old. Followup ranged from 5 to 9 years in 65 patients, 10 to 14 years in 25 and 15 to 18 years in 12. RESULTS
MATERIAL AND METHODS
The 102 patients with reflux alone were managed on a regimen of multiple micturition, intermittent chemotherapy and some ablative operation for 5 to 18 years. An additional 19 patients with inadequate followup and those in whom reflux was associated with ureteral duplications, vesical diverticula, urethral valves, neurogenic bladder or iatrogenic causes were excluded from the study. The patients included 35 boys and 67 girls. Reflux was bilateral in 30 (80 per cent) boys and 37 (55 per cent) girls, making a total of 167 ureters. The boys were referred mainly during the first year of life and 80 per cent of them were seen by the age of 3 years. The maximum incidence in girls occurred at the age of 7 years, with only a quarter of them having been seen by the age of 3 years (see figure). Urinary tract infections were present in 25 (71 per cent) boys and 62 (93 per cent) girls. Information was tabulated from the clinical history and results of previous urinalyses, excretory urograms (IVPs) and micturition cystourethrograms. All patients were assessed finally by blood pressure and blood urea estimations, microscopy and urine cultures, IVP and, if reflux was present on the preceding occasion, micturition cystourethrograms. At final followup 19 patients were 5 to 9 years old, 37 were 10 to 14 years Accepted for publication October 10, 1975. * Current address: Urological Clinic, St. Vincent's Hospital, Melbourne, Australia. t Current address: Department of Radiology, Royal Children's Hospital, Melbourne, Australia. :j:Requests for reprints: Department of Surgery, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614.
Natural cessation of reflux. Of 167 ureters 83 displayed natural cessation of reflux. Factors influencing cessation were the caliber of the ureter and the age of the patient at the time of diagnosis. Reflux ceased in 65 (66 per cent) of98 normal caliber ureters, that is those measuring up to 1.0 cm. maximum width on micturition cystourethrography. Cessation occurred in 15 (33 per cent) of 48 moderately dilated ureters (LO to 2.0 cm. maximum width on micturition cystourethrography) and in only 3 (14 per cent) of 21 grossly dilated ureters (more than 2.0 cm. maximum width on micturition cystourethrography). Thus, of 69 dilated ureters 18 (26 per cent) ceased to reflux. Ureteral dilatation often diminished despite persistent reflux. Of the dilated ureters 15 (22 per cent) retained reflux but reverted to normal caliber and 36 (52 per cent) retained reflux and dilatation at the end of followup. Of 21 ureters initially grossly dilated 5 became moderately dilated and 1 reached normal caliber wi:th persistent reflux. Of 33 normal caliber ureters with persistent reflux only 2 were dilated, both in a girl with an occult neurogenic bladder disturbance discovered later on cystography. Over-all, 43 (42 per cent) of the patients were free of reflux. Unilateral reflux ceased in 24 (65 per cent) of 37 patients. Of 31 patients with bilateral reflux in normal caliber ureters 16 (50 per cent) became free of reflux but in only 3 (9 per cent) of 34 patients with bilateral dilated ureters did reflux cease. Age and cessation of reflux: The younger the patient at the time of presentation the greater the likelihood of early cessation of reflux. Of 22 ureters in patients seen during the first year of life reflux ceased in 15 (68 per cent) by the time the patient was 14 years old. In 7 of these ureters reflux ceased before the patient was 6 years old and in 13 by the time the patient was 9 years old. Of 18 ureters in patients between 1 and 2 years of age 8 (44 per cent) ceased to reflux by the time the patient was 14 years old. Reflux ceased in 2 of these 8 ureters before the patient was 6 years old. Of 19 ureters in patients between 2 and 3 years of age none lost reflux before
728
lil
N!JMBS:f.! of PATlENTS
0
6
10 YEI.J~S OF AGE
Graph shows age of patients at time of diagnosis of reflux and maximum incidence in boys during first year of life and in girls at 7 years of age.
the patient was 6 years oid and only 7 (37 per cent) ceased to reflux by the time the patient was 14 years old. Of 117 ureters in patients between 3 and 12 years of age 31 (26 per cent) ceased to have reflux by the time the patient was 14 years old. Of the total 83 ureters in which reflux ceased 22 (27 per cent) did so after the was 14 years old. on renal parenchyma. In 120 of the 167 refluxing ureters adequate to cornpare the renal parenchyma at the time of diagnosis and were available. The criteria of Hodson and associates were used to assess renal length. 2 Tracings of the renal outlines and inlines (pelviocaliceal systems) were made to detect renal scarring, focal and general thinning, and caliceal clubbing. Of 76 kidneys considered normal at 16 (21 per cent) in 13 patients showed deterioration during Of 44 recognized as abnormal at the time of diagnosis 29 (66 per cent) underwent further deterioration. Of the 45 that deteriorated 27 ,,vere associated with persistent reflux and ureteral reflux ceased in 18. Deterioration was seen in with either normal caliber or dilated ureters. the 16 kidneys that were normal revealed that the ureters were dilated in 13 ( 4 and 9 . All of these patients were seen before were 7 years old and 9 of them before the of 3 years. Reflux was bilateral in 11 of the 13 patients was present for 3 years in l and from 6 to 13 years i.,, 12. Twelve of the 13 had documented verse features of infection and dilated ureters. There were num_erous instances of reflux. Two presence of 1 after contralateral ,,,..,p,.,1·,nnv and 1 vvith bilateral reflux. There were 6 with absence of and 3 with all of which had persistent ureteral reflux. One vesicoureteral reflux had ceased also There were 12 patients with elevated blood urea levels at the end of followup but 10 of them had had elevated levels at the time of diagnosis. All children had bilateral reflux except 1 who had unilateral reflux and hypertension. Hypertension (more than 140 mm. Hg systolic or 90 mm. Hg diastolic) developed in 10 patients. Of these 10 children 3 had elevated blood urea levels, 3 had urinary infection at final followup and 3 of the 4 kidneys undergoing contraction were in hypertensive patients. Reflux and urinary infection. Infection was diagnosed by the growth of a single strain of organism in significant numbers from a midstream or catheter specimen of urine. After diagnosis 20 boys and 20 girls had no further documented infections.
2.6
in 42 3.7 There were 6 patients with incomplete At the end of 2 and 10 girls all of whom exhibited reflux. Infection was mainly associated with persistent reflux. No episodes of infection occurred in in whom reflux ceased but there were 12 of 29 girls (41 per cent) who had further infection after reflux ceased. Urinary infection and renal damage: Renal damage was more likely in patients with proved infection. In 25 of the 56 patients in whom infection was diagnosed lesions developed in 35 kidneys, 7 in 5 and 28 in 20 girls. In 7 of the 40 patients free of further infection 10 kidneys underwent deterioration, 5 in 4 boys and 5 in 3 girls. Renal damage was just as likely in patients with 1 infection episode as in those with numerous episodes. For example, 18 renal lesions developed in 20 patients who had 1 episode of infection, while 6 lesions occurred in 9 patients who had 6 or more episodes. Although renal lesions appeared during the entire followup period, proved episodes of infection in the presence of reflux were more common during the first 5 years after diagnosis. After this time less than half of the patients followed had infection. DISCUSSION
Factors in renal damage. The incidence of renal damage at the time of diagnosis in children with reflux is high. 120 kidneys with reflux in our series 44 (36 per cent) were abnom1al at diagnosis. In other series 54 per cent of the kidneys 3 and 15 to 35 per cent of the patients with reflux had scarring. H Lesions in 21 per cent of initially normal kidneys and in 66 per cent of those initially abnormal, compared to 12.5 and 62.5 per cent, respectively, reported elsewhere. 7 Renal damage in normal kidneys was seen usually in those patients with dilated ureters but deterioration in initially abnormal kidneys occurred irrespective of ureteral caliber. 8 Renal lesions were more numerous when infection was recorded and the latter was more common in the presence of reflux. The appearance of renal lesions at the same rate throughout the years of suggested that the longer reflux the more likely renal damage was to occur. The development of lesions in normal kidneys to reflux and infection indicated that antireflux operation should improve their outlook. Absence of further deterioration after an antireflux operation 3• 6 has been observed in these those patients in whom reflux will cease within a short time after dilatation or internal has been required in 20 to 60 per non-cessation of reflux as the sole criterion operation 58 per cent of our would If recurrence of infection were the indication the same number of (60 per cent) The
ureter ceasing to guide upon which to determine an ""Qrrwr·n appearance of the ureteraI orifice 11 can be useful in this decision. Excluding those orifices in which reflux is most likely to cease an operation appears indicated if infection occurs after diagnosis. An exception may be made in babies in whom the kidney and ureteral caliber are near normal. 8 Reflux and infection. Although sterile reflux has been reported to cause renal damage 12 or even end stage renal failure, 13 other experimental and clinical evidence has shown it can be harmless. 10 • 14 ' 15 In our series infection in patients with reflux was more common during the first 5 years after diagnosis whereas renal iesion appeared throughout followup. The failure to note infection in long-standing reflux and the long time ~o,,v-,v~
730
LENAGHAN AND ASSOCIATES
taken for radiologic evidence of damage to appear after infection 7 suggest that some examples of renal damage in apparently sterile reflux may have an infective basis. Occurrence of urinary infections is recognized after the cessation or control of reflux and incidences from 20 to 58 per cent have been recorded. 1 •· 18 In our series no infections occurred after cessation in boys but it was noted in 41 per cent of the girls. Reflux was more common in boys during infancy and in girls during childhood. A similar relation has been noted for clinical and asymptomatic urinary infections, which has led to the consideration that infection may cause reflux. 19 Descriptions of the pathology of the intravesical portion of the ureter permitting reflux indicate a muscular defect without evidence of damage caused by chronic infection. 20 • 21 Experimental and clinical observations have shown that acute cystitis may cause reflux. 22 • 23 However, this must be a rare cause in children with reflux when the urine is sterile, often on more than 1 occasion, and accompanied by cystoscopic abnormalities of the ureteral orifices. Reflux and infection appear to have no etiologic relation in children but renal damage requires their simultaneous presence. ADDENDUM
These studies record the results of non-operative management of vesicoureteral reflux during a 20-year span when present day drugs were not so readily available and regimens of chemotherapy were experimental and emerging. With the introduction of low dose prophylactic therapy as now prescribed, recurrent infections and renal scarring may have been considerably reduced. These factors should be considered when drawing conclusions from the facts recorded herein.
8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20. 21.
REFERENCES
1. Stephens, F. D.: Preliminary followup study of 101 children with reflux treated conservatively. In: Renal Infection and Renal Scarring, 2nd ed. Edited by P. K. Smith and K. F. Fairley. Australia: Melbourne Mercedes Publishing Services, p. 283, 1970. 2. Hodson, C. J., Drewe, J. A., Karn, M. N. and King, A.: Renal size in normal children. A radiographic study during life. Arch. Dis. Child., 37: 616, 1962. 3. Hutch, J. A., Smith, D.R. and Osborne, R.: Review of a series of ureterovesicoplasties. J. Urol., 100: 285, 1968. 4. Brannan, W., Ochsner, M. G., Rosencrantz, D. R., Whitehead, C. M., Jr. and Goodier, E. H.: Experiences with vesicoureteral reflux. J. Urol., 109: 46, 1973. 5. Williams, D. I. and Eckstein, H.B.: Surgical treatment of reflux in children. Brit. J. Urol., 37: 13, 1965. 6. Dwoskin, J. Y. and Perlmutter, A. D.: Vesicoureteral reflux in children: a computerized review. J. Urol., 109: 888, 1973. 7. Filly, R., Friedland, G. W., Govan, D. E. and Fair, W. R.:
22. 23.
Development and progression of clubbing and scarring in children with recurrent urinary tract infections. Radiology, 113: 145, 1974. Rolleston, G. L., Shannon, F. T. and Utley, W. L.: Relationship of infantile vesicoureteric reflux to renal damage. Brit. Med. J., 1: 460, 1970. Allison, R. C. and Leadbetter, G. W., Jr.: The effect ofurethrotomy on vesicoureteral reflux. J. Urol., 108: 480, 1972. King, L. R., Surian, M. A., Wendel, R. M. and Burden, J. J.: Vesicoureteral reflux: a classification based on cause and the results of treatment. J.A.M.A., 203: 169, 1968. Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969. Hutch, J. A. and Smith, D. R.: Sterile reflux: report of 24 cases. Urol. Int., 24: 460, 1969. Salvatierra, 0., Jr., Kountz, S. L. and Belzer, F. 0.: Primary vesicoureteral reflux and end-stage renal disease. J.A.M.A., 226: 1454, 1973. Lenaghan, D., Cass, A. S., Cussen, L. J. and Stephens, F. D.: Long-term effect of vesicoureteral reflux on the upper urinary tract of dogs: I. Without urinary infection. J. Urol., 107: 755, 1972. Thompson, I. M., Karow, W. F. and Ross, G., Jr.: Long-term results of ureteral reimplantation for trauma. J. Urol., 102: 308, 1969. Kendall, A. R. and Karafin, L.: Urinary tract infection in children: fact and fantasy. J. Urol., 107: 1068, 1972. Amar, A. D. and Singer, B.: Vesicoureteral reflux: a 10-year study of 280 patients. J. Urol., 109: 999, 1973. Govan, D. E. and Palmer, J. M.: Urinary tract infection in children. The influence of successful antireflux operations in morbidity from infection. Pediatrics, 44: 677, 1969. Stamey, T. A.: Urinary Infections. Baltimore: The Williams & Wilkins Co., chapt. 5, 1972. Stephens, F. D. and Lenaghan, D.: The anatomical basis and dynamics of vesicoureteral reflux. J. Urol., 87: 669, 1962. Tanagho, E. A., Guthrie, T. H. and Lyon, R. P.: The intravesical ureter in primary reflux. J. Urol., 101: 824, 1969. Auer, J. and Seager, L. D.: Experimental local bladder edema causing urine reflux into ureters and kidneys. Proc. Soc. Exp. Biol. Med., 35: 361, 1936. · Hanley, H. G.: Pyelonephritis and lower urinary-tract inflammation. Lancet, 1: 22, 1963. COMMENT
The urological surgeon should have these facts clearly in mind when recommending treatment for the patient with reflux. Modern chemotherapy and antibiotic treatment should improve the results by lessening the recurrence of infection and the incidence of renal damage. Certainly all patients with low grades of reflux who have no renal damage deserve a period of observation on a good chemotherapeutic regimen before considering surgical correction of reflux.
Robert D. Jeffs The Johns Hopkins Hospital Baltimore, Maryland
