294
Leading articles Chemotherapy of urinary tract infections in children
Treatment of urinary tract infections in children has in the past been complicated and obscured by two diagnostic problems. Firstly, the non-specific nature of the presentation was not appreciated, thus symptoms normally related to the urinary tract such as frequency, dysuria or loin pain are often absent whereas fever, convulsions, gastrointestinal upset, failure to thrive or odorous urine may be the presenting feature especially in infants and young children. More general understanding of this has resulted in earlier diagnosis (Smellie, 1970). Accurate diagnosis obviously depends on obtaining an uncontaminated urine specimen. Until recent years the standard method was collection into a sterile receiver (clean catch) or into a plastic bag applied to the perineum. Both these methods are open to the possibility of unacceptable contamination although the perineal bag method is much more reliable if the infant can be kept upright during the whole period of collection (Smellie & Normand, 1975). A negative bag culture is valuable in an infant, but suprapubic needle aspiration is often necessary to confirm a doubtful result and in trained hands this method is safe and reliable and should always be used in an ill child where a rapid result is required (Hardy, Furnell & Brumfitt, 1976). In spina bifida children with an empty bladder a small catheter, No. 8-12 FG of the disposable plastic variety should be used to obtain a specimen and indeed this method is also indicated where confirmation of a urinary tract infection is required and when the bladder is impalpable. It is important that a urine specimen should be taken in any 'ill child' before commencing chemotherapy because of the possible co-existence of a covert urinary tract infection. Most urinary tract infections in children are due to Escherichia coli and are sulphonamide sensitive (85% first infections and 60 to 70% of repeat infections). They are usually due to one of a small proportion of serotypes which are present in the lower bowel and perineum as regular commensals and there is a close correlation between the organisms cultured from the bladder at the time of infection and from a rectal swab both in serotype and antibiotic sensitivity. A smaller proportion are due to Streptococcus faecalis and Proteus species. Proteus infections are
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
Hong Kong TB Treatment Services/British Medical Research Council. Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Tubercle 56: 81-96 (1975). Kent, P. W., Fox, W., Miller, A. B., Nunn, A. J., Tall, R. & Mitchison, D. A. The therapy of pulmonary tuberculosis in Kenya: a comparison of the results achieved in controlled clinical trials with those achieved by the routine treatment services. Tubercle 51: 24-38 (1970). Lesobre, R., Ruffino, J., Teyssier, L., Achard F., & Brefort, C. Les icteres au cours du traitement par la rifampicine (12 observations). Revue de la tuberculose et de Pneumonologie 33: 393403 (1969). Matthews, J. H. Pyrazinamide and isoniazid used in the treatment of pulmonary tuberculosis. American Review of Respiratory Disease 81: 348-51 (1960). McCune, R. M., Feldman, F. M., Lambert, H. P. & McDermott, W. Microbial persistence. The capacity of tubercle bacilli to survive sterilisation in mouse tissues. Journal of Experimental Medicine 123: 445-68 (1966). McDermott, W., Ormond, K., Muschenheim, C , Deuchle, K., McCune, R. M. & Tompsett, R. Pyrazinamide-isoniazid in tuberculosis. American Review of Tuberculosis 69: 319-33 (1954). Medical Research Council. Report by their Tuberculosis Chemotherapy Trials Committee. Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation. Tubercle 43: 201-67 (1962). Mitchison, D. A. Bacteriological mechanisms in recent controlled chemotherapy studies. Bulletin of the International Union against Tuberculosis 43: 322-31 (1970). Roussel, G. XV Congres de Phtisiologie et de Pneumologie d'Argentine, 23-28 November (1975) U.S. Public Health Service Tuberculosis Therapy Trial. Hepatic toxicity of pyrazinamide used with isoniazid in tuberculous patients. American Review of Respiratory Disease80:375-S7 (1959o). U.S. Public Health Service Tuberculosis Therapy Trial. Sequential use of paired combinations of isoniazid, streptomycin, para-aminosalicylic acid and pyrazinamide. American Review of Respiratory Disease 80: 627-40 (1959*). Velu, S., Andrews, R. H., Angel, J. H., Devadatta, S., Fox, W., Jacob, P. G., Nair, C. N. & Ramakrishnan, C. V. Streptomycin plus pyrazinamide in the treatment of patients excreting isoniazidresistant tubercle bacilli, following previous chemotherapy. Tubercle 42: 136-47 (1961). Velu, S., Dawson, J. J. Y., Devadatta, S., Fox, W., Kulkarni, K. G., Mohan, K., Ramakrishnan, C. V. & Stott, H. A controlled comparison of streptomycin plus pyrazinamide and streptomycin plus PAS in the re-treatment of patients excreting isoniazJd-resistant organisms. Tubercle 45: 144-59 (1964).
Leading articles more commonly seen in boys (Maskell, Pead & Hallett, 1975) and investigation of recurrent proteus infections is important as a high proportion are associated with stone formation (Gaches, Gordon, Shore & Roberts,
295
to one of the cephalosporin drugs or nalidixic acid. Follow-up and maintenance treatment
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
There appears to be an increased tendency to 1975; Ghazali, 1975). Pseudomonas aeruginosa re-infection in children for several months infections are usually post-instrumental in after the acute episode, and such infections origin and associated with chronic bladder are often asymptomatic. There must therefore dysfunction—for example the neurogenic be a choice in subsequent management bladder of spina bifida. They are usually between close bacteriological follow-up and multi-resistant. maintenance therapy for 6 months. Some clinicians prefer to culture the urine on a monthly basis for 3 months and thereafter Treatment Treatment of choice for the acute infection is every 2 months for a further 6 months or so with the first line drugs, sulphonamide, nitro- treating such infections that arise as single furantoin or co-trimoxazole. For sulphona- episodes. Others favour maintenance chemomides, sulphamezathine (sulphadimidine) therapy. Children tolerate sulphonamides and 100 mg/kg/day in 4 doses, or sulphafurazole co-trimoxazole remarkably well over a long in the same dose, nitrofurantoin 5-5 mg/kg/day period. The suggested dosage is one third of in 4 doses, or co-trimoxazole 40 to 80 mg the therapeutic dose and should continue for of trimethoprin and 200 to 400 mg of sulpha- at least 6 months. methoxazole 12-hourly. Nitrofurantoin has the theoretical disadvan- Investigation tage of a low tissue concentration being most The counsel of perfection is that all children effective in the lower urinary tract due to should be fully investigated after one proven concentration of the drug in the renal tubule. infection. Certainly this applies to boys in However, it is remarkably effective clinically, whom there is a high incidence of underlying even in those children with systemic upset urinary tract abnormality. In practice girls suggesting serious upper tract involvement are generally referred for investigation after but vomiting may prevent adequate adminis- more than one proven infection. Investigation tration. Sulphonamides are potentially danger- in this context is mainly radiological and both ous in the neonatal period and perhaps better excretion urography and micturating cystoavoided. Co-trimoxazole has the advantage graphy should be carried out to exclude of easy administration (12-hourly). anatomical and functional anomalies of the In infants seriously ill, blood culture often urinary tract and to exclude reflux. Endoscopy reveals a septicaemia due to the same organ- has more limited value and is generally isms present in the urine but treatment must reserved for cases where there is radiological commence often before sensitivities are avail- evidence of a lower tract obstruction. able. Co-trimoxazole or parenteral ampicillin Serious unsuspected abnormalities of the are probably the first line drugs in this context urinary tract are found in 8 to 10% of bacteriwith a change to gentamicin in the light of uric children and some anomaly in almost half. the sensitivity report. About one-third of children demonstrate In children a 7- to 10-day course of treatment vesico-ureteric reflux and coexistence of is usually recommended although in most reflux with infection in infants and young cases symptoms resolve and the urine is children often result in renal scarring (reflux sterilized after thefirst48 h. There is increasing nephropathy) if untreated. evidence that in adult infections a 2- to 3-day Persistent bacteriuria after 48 h treatment course of treatment is equally effective as the is unusual in children with a normal urinary longer (7 to 10 days) course (Charlton, tract and is an added indication for full Crowther, Davies, Dynes & Hayward, 1976), investigation. Proteus infections are especially but it remains to be proved whether the short significant as there is a high incidence of course can be equally applied to the treatment calculous disease (Gaches et al., 1975; of children. In clinical practice it is seldom Ghazali, 1975). In prepubertal uncircumsized necessary to change to second line drugs boys however the preputial sac may be the unless of course systemic infection with origin of such infections (Maskell et al., 1975). septicaemia has occurred. In the event of Treatment of underlying urinary tract relapsing infections with change of sensitivity abnormality and anti-reflux surgery requires pattern it may however be necessary to change maintenance chemotherapy for several months
296
Leading articles
after treatment as well as a prophylactic cover during the operative period. During the immediate post-operative period parenteral ampicillin is usually favoured with a return to oral therapy with the appropriate agent as soon as possible—usually within 48 h. Screening for bacteriuria
N. SLADE Department of Urology, Southmead Hospital, Bristol, England
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
This has been well documented (Kunin, Deutscher & Paquin, 1974; Savage, Wilson, McHardy, Dewar & Fee, 1969; Asscher et al., 1973) but applied in most cases to school girls of 5 years or over. The incidence of bacteriuria was 1 to 2% and follow-up so far has revealed no deterioration in renal function except in the Cardiff (Asscher) series. However, they had all been treated. Retrospective study revealed that in many of these so-called asymptomatic bacteriurics, previous symptomatology had occurred (covert infection). It would appear that screening programmes on a national scale would be prohibitively expensive and unlikely to be rewarding. In any case it must be applied to the 'pre-school' age if reflux nephropathy is to be prevented. On present evidence it would seem that maintenance of a high index of suspicion in the unwell infant and a very close follow-up of all confirmed infections in children is likely to yield the best results in prevention of serious morbidity. Because of the increased familial incidence of urinary tract infection and reflux (Mulcahy, Kelalis, Stickler & Burke, 1970) regular screening of siblings and female children with a family history of reflux nephropathy is necessary.
References Asscher, A. W., Jones, R. V., Mellers S., McClachan, M. S. S., Sussman, M., Harrison, S. S., Johnston, H. H., Sleight, G. & Fletcher, E. W. Screening for asymptomatic urinary tract infections amongst schoolgirls. The Lancet ii: 1-3 (1973). Chariton, C , Crowther, A., Davies, J. G., Dynes, J. & Hayward, M. W. A. Three-day and ten-day chemotherapy for urinary tract infections in general practice. British Medical Journal i: 124-6 (1976). Gaches, C. G. C , Gordon, I. R. S., Shore, D. F. & Roberts, J. B. M. Urinary lithiasis in childhood in the Bristol Clinical Area. British Journal of Urology 47: 109-16 (1975). Ghazali, S. Childhood urolithiasis in the United Kingdom and Eire. British Journal of Urology 47: 739-43 (1975). Hardy, J. D., Furnell, P. M. & Brumfitt, W. Comparison sterile bag, clean catch and suprapubic aspiration in the diagnosis of urinary infection. British Journal of Urology 49: 27983 (1976). Kunin, C. M., Deutscher, R. & Paquin, A. Urinary tract infection in school children: epidemiological, clinical and laboratory study. Medicine, Baltimore 43: 91 (1964). Maskell, R., Pead, L. & Hallett, R. M. Urinary pathogens in the male. British Journal of Urology 47: 691-4 (1975). Mulcahy, J. J., Kelalis, P. P., Stickler, G. B. & Burke, E. C. Familial vesicoureteral reflux. Journal of Urology 104: 762 (1970). Savage, D. C. L., Wilson, M. I., McHardy, M., Dewar, D. A. E. & Fee, W. M. Covert bacteriuria of childhood: A clinical and epidemiological study. Archives of Diseases in Childhood 48:8-20(1973). Smellie, J. M. Acute urinary tract infection in children. British Medical Journal iv: 97-100 (1970). Smellie, J. M. & Norman, I. C. S. Bacteriuria, reflux and renal scarring. Archives of Disease in Childhood 50: 581-5 (1975).
Leading articles Chemotherapy of urinary tract infections in children
Treatment of urinary tract infections in children has in the past been complicated and obscured by two diagnostic problems. Firstly, the non-specific nature of the presentation was not appreciated, thus symptoms normally related to the urinary tract such as frequency, dysuria or loin pain are often absent whereas fever, convulsions, gastrointestinal upset, failure to thrive or odorous urine may be the presenting feature especially in infants and young children. More general understanding of this has resulted in earlier diagnosis (Smellie, 1970). Accurate diagnosis obviously depends on obtaining an uncontaminated urine specimen. Until recent years the standard method was collection into a sterile receiver (clean catch) or into a plastic bag applied to the perineum. Both these methods are open to the possibility of unacceptable contamination although the perineal bag method is much more reliable if the infant can be kept upright during the whole period of collection (Smellie & Normand, 1975). A negative bag culture is valuable in an infant, but suprapubic needle aspiration is often necessary to confirm a doubtful result and in trained hands this method is safe and reliable and should always be used in an ill child where a rapid result is required (Hardy, Furnell & Brumfitt, 1976). In spina bifida children with an empty bladder a small catheter, No. 8-12 FG of the disposable plastic variety should be used to obtain a specimen and indeed this method is also indicated where confirmation of a urinary tract infection is required and when the bladder is impalpable. It is important that a urine specimen should be taken in any 'ill child' before commencing chemotherapy because of the possible co-existence of a covert urinary tract infection. Most urinary tract infections in children are due to Escherichia coli and are sulphonamide sensitive (85% first infections and 60 to 70% of repeat infections). They are usually due to one of a small proportion of serotypes which are present in the lower bowel and perineum as regular commensals and there is a close correlation between the organisms cultured from the bladder at the time of infection and from a rectal swab both in serotype and antibiotic sensitivity. A smaller proportion are due to Streptococcus faecalis and Proteus species. Proteus infections are
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
Hong Kong TB Treatment Services/British Medical Research Council. Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Tubercle 56: 81-96 (1975). Kent, P. W., Fox, W., Miller, A. B., Nunn, A. J., Tall, R. & Mitchison, D. A. The therapy of pulmonary tuberculosis in Kenya: a comparison of the results achieved in controlled clinical trials with those achieved by the routine treatment services. Tubercle 51: 24-38 (1970). Lesobre, R., Ruffino, J., Teyssier, L., Achard F., & Brefort, C. Les icteres au cours du traitement par la rifampicine (12 observations). Revue de la tuberculose et de Pneumonologie 33: 393403 (1969). Matthews, J. H. Pyrazinamide and isoniazid used in the treatment of pulmonary tuberculosis. American Review of Respiratory Disease 81: 348-51 (1960). McCune, R. M., Feldman, F. M., Lambert, H. P. & McDermott, W. Microbial persistence. The capacity of tubercle bacilli to survive sterilisation in mouse tissues. Journal of Experimental Medicine 123: 445-68 (1966). McDermott, W., Ormond, K., Muschenheim, C , Deuchle, K., McCune, R. M. & Tompsett, R. Pyrazinamide-isoniazid in tuberculosis. American Review of Tuberculosis 69: 319-33 (1954). Medical Research Council. Report by their Tuberculosis Chemotherapy Trials Committee. Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation. Tubercle 43: 201-67 (1962). Mitchison, D. A. Bacteriological mechanisms in recent controlled chemotherapy studies. Bulletin of the International Union against Tuberculosis 43: 322-31 (1970). Roussel, G. XV Congres de Phtisiologie et de Pneumologie d'Argentine, 23-28 November (1975) U.S. Public Health Service Tuberculosis Therapy Trial. Hepatic toxicity of pyrazinamide used with isoniazid in tuberculous patients. American Review of Respiratory Disease80:375-S7 (1959o). U.S. Public Health Service Tuberculosis Therapy Trial. Sequential use of paired combinations of isoniazid, streptomycin, para-aminosalicylic acid and pyrazinamide. American Review of Respiratory Disease 80: 627-40 (1959*). Velu, S., Andrews, R. H., Angel, J. H., Devadatta, S., Fox, W., Jacob, P. G., Nair, C. N. & Ramakrishnan, C. V. Streptomycin plus pyrazinamide in the treatment of patients excreting isoniazidresistant tubercle bacilli, following previous chemotherapy. Tubercle 42: 136-47 (1961). Velu, S., Dawson, J. J. Y., Devadatta, S., Fox, W., Kulkarni, K. G., Mohan, K., Ramakrishnan, C. V. & Stott, H. A controlled comparison of streptomycin plus pyrazinamide and streptomycin plus PAS in the re-treatment of patients excreting isoniazJd-resistant organisms. Tubercle 45: 144-59 (1964).
Leading articles more commonly seen in boys (Maskell, Pead & Hallett, 1975) and investigation of recurrent proteus infections is important as a high proportion are associated with stone formation (Gaches, Gordon, Shore & Roberts,
295
to one of the cephalosporin drugs or nalidixic acid. Follow-up and maintenance treatment
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
There appears to be an increased tendency to 1975; Ghazali, 1975). Pseudomonas aeruginosa re-infection in children for several months infections are usually post-instrumental in after the acute episode, and such infections origin and associated with chronic bladder are often asymptomatic. There must therefore dysfunction—for example the neurogenic be a choice in subsequent management bladder of spina bifida. They are usually between close bacteriological follow-up and multi-resistant. maintenance therapy for 6 months. Some clinicians prefer to culture the urine on a monthly basis for 3 months and thereafter Treatment Treatment of choice for the acute infection is every 2 months for a further 6 months or so with the first line drugs, sulphonamide, nitro- treating such infections that arise as single furantoin or co-trimoxazole. For sulphona- episodes. Others favour maintenance chemomides, sulphamezathine (sulphadimidine) therapy. Children tolerate sulphonamides and 100 mg/kg/day in 4 doses, or sulphafurazole co-trimoxazole remarkably well over a long in the same dose, nitrofurantoin 5-5 mg/kg/day period. The suggested dosage is one third of in 4 doses, or co-trimoxazole 40 to 80 mg the therapeutic dose and should continue for of trimethoprin and 200 to 400 mg of sulpha- at least 6 months. methoxazole 12-hourly. Nitrofurantoin has the theoretical disadvan- Investigation tage of a low tissue concentration being most The counsel of perfection is that all children effective in the lower urinary tract due to should be fully investigated after one proven concentration of the drug in the renal tubule. infection. Certainly this applies to boys in However, it is remarkably effective clinically, whom there is a high incidence of underlying even in those children with systemic upset urinary tract abnormality. In practice girls suggesting serious upper tract involvement are generally referred for investigation after but vomiting may prevent adequate adminis- more than one proven infection. Investigation tration. Sulphonamides are potentially danger- in this context is mainly radiological and both ous in the neonatal period and perhaps better excretion urography and micturating cystoavoided. Co-trimoxazole has the advantage graphy should be carried out to exclude of easy administration (12-hourly). anatomical and functional anomalies of the In infants seriously ill, blood culture often urinary tract and to exclude reflux. Endoscopy reveals a septicaemia due to the same organ- has more limited value and is generally isms present in the urine but treatment must reserved for cases where there is radiological commence often before sensitivities are avail- evidence of a lower tract obstruction. able. Co-trimoxazole or parenteral ampicillin Serious unsuspected abnormalities of the are probably the first line drugs in this context urinary tract are found in 8 to 10% of bacteriwith a change to gentamicin in the light of uric children and some anomaly in almost half. the sensitivity report. About one-third of children demonstrate In children a 7- to 10-day course of treatment vesico-ureteric reflux and coexistence of is usually recommended although in most reflux with infection in infants and young cases symptoms resolve and the urine is children often result in renal scarring (reflux sterilized after thefirst48 h. There is increasing nephropathy) if untreated. evidence that in adult infections a 2- to 3-day Persistent bacteriuria after 48 h treatment course of treatment is equally effective as the is unusual in children with a normal urinary longer (7 to 10 days) course (Charlton, tract and is an added indication for full Crowther, Davies, Dynes & Hayward, 1976), investigation. Proteus infections are especially but it remains to be proved whether the short significant as there is a high incidence of course can be equally applied to the treatment calculous disease (Gaches et al., 1975; of children. In clinical practice it is seldom Ghazali, 1975). In prepubertal uncircumsized necessary to change to second line drugs boys however the preputial sac may be the unless of course systemic infection with origin of such infections (Maskell et al., 1975). septicaemia has occurred. In the event of Treatment of underlying urinary tract relapsing infections with change of sensitivity abnormality and anti-reflux surgery requires pattern it may however be necessary to change maintenance chemotherapy for several months
296
Leading articles
after treatment as well as a prophylactic cover during the operative period. During the immediate post-operative period parenteral ampicillin is usually favoured with a return to oral therapy with the appropriate agent as soon as possible—usually within 48 h. Screening for bacteriuria
N. SLADE Department of Urology, Southmead Hospital, Bristol, England
Downloaded from http://jac.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on March 31, 2015
This has been well documented (Kunin, Deutscher & Paquin, 1974; Savage, Wilson, McHardy, Dewar & Fee, 1969; Asscher et al., 1973) but applied in most cases to school girls of 5 years or over. The incidence of bacteriuria was 1 to 2% and follow-up so far has revealed no deterioration in renal function except in the Cardiff (Asscher) series. However, they had all been treated. Retrospective study revealed that in many of these so-called asymptomatic bacteriurics, previous symptomatology had occurred (covert infection). It would appear that screening programmes on a national scale would be prohibitively expensive and unlikely to be rewarding. In any case it must be applied to the 'pre-school' age if reflux nephropathy is to be prevented. On present evidence it would seem that maintenance of a high index of suspicion in the unwell infant and a very close follow-up of all confirmed infections in children is likely to yield the best results in prevention of serious morbidity. Because of the increased familial incidence of urinary tract infection and reflux (Mulcahy, Kelalis, Stickler & Burke, 1970) regular screening of siblings and female children with a family history of reflux nephropathy is necessary.
References Asscher, A. W., Jones, R. V., Mellers S., McClachan, M. S. S., Sussman, M., Harrison, S. S., Johnston, H. H., Sleight, G. & Fletcher, E. W. Screening for asymptomatic urinary tract infections amongst schoolgirls. The Lancet ii: 1-3 (1973). Chariton, C , Crowther, A., Davies, J. G., Dynes, J. & Hayward, M. W. A. Three-day and ten-day chemotherapy for urinary tract infections in general practice. British Medical Journal i: 124-6 (1976). Gaches, C. G. C , Gordon, I. R. S., Shore, D. F. & Roberts, J. B. M. Urinary lithiasis in childhood in the Bristol Clinical Area. British Journal of Urology 47: 109-16 (1975). Ghazali, S. Childhood urolithiasis in the United Kingdom and Eire. British Journal of Urology 47: 739-43 (1975). Hardy, J. D., Furnell, P. M. & Brumfitt, W. Comparison sterile bag, clean catch and suprapubic aspiration in the diagnosis of urinary infection. British Journal of Urology 49: 27983 (1976). Kunin, C. M., Deutscher, R. & Paquin, A. Urinary tract infection in school children: epidemiological, clinical and laboratory study. Medicine, Baltimore 43: 91 (1964). Maskell, R., Pead, L. & Hallett, R. M. Urinary pathogens in the male. British Journal of Urology 47: 691-4 (1975). Mulcahy, J. J., Kelalis, P. P., Stickler, G. B. & Burke, E. C. Familial vesicoureteral reflux. Journal of Urology 104: 762 (1970). Savage, D. C. L., Wilson, M. I., McHardy, M., Dewar, D. A. E. & Fee, W. M. Covert bacteriuria of childhood: A clinical and epidemiological study. Archives of Diseases in Childhood 48:8-20(1973). Smellie, J. M. Acute urinary tract infection in children. British Medical Journal iv: 97-100 (1970). Smellie, J. M. & Norman, I. C. S. Bacteriuria, reflux and renal scarring. Archives of Disease in Childhood 50: 581-5 (1975).
