Acute focal bacterial nephritis with vesicoureteral reflux in infants CURRENT STATUS: POSTED

Acute focal bacterial nephritis (AFBN) is a seldom infection in children kidney disease,Vesicoureteral reflux(VUR) often exist in infants who are easy to have urinary tract infection(UTI).In this study,we summarize the clinical features ,imaging and therapy. ratio;APN: acute pyelonephritis.


Abstract Background
Acute focal bacterial nephritis (AFBN) is a seldom infection in children kidney disease,Vesicoureteral reflux(VUR) often exist in infants who are easy to have urinary tract infection (UTI).In this study,we summarize the clinical features ,imaging and therapy. Methods eleven patients with AFBN and VUR aged from two months to eight months treated at this hospital from January 2017 to August 2019 were reviewed.The manifestations,urine and blood tests, imagings,treatments of patients were analyzed retrospectively.

Results
Fever was the common symptom,blood CRP was higher than normal(25 mg/L-200 mg/L),The percentage of neutrophils in blood was 52%-85%.The ratio of neutrophils to lymphocytes was 1.39-11.6,Routine urine microscopic examination of leukocyte was +∽3+/HP,Urine culture samples were 42, 34 samples were positive, the positive rate was 80.95%.Diagnosis was set by CT combined MCU.Enhanced CT conducted for all patients showed hypoperfused wedged-shaped or round and space-occupying lesions in kidney.MCU conducted showed I-V grade VUR in single or both sides.9 cases were treated with prophylactic antibiotics, DxHA injection was operated on 1 case, cohen operation for another patient.Relapses were rarely occur after insisting on treatment.
Conclusion AFBN in children are rare and associated with VUR. Patients with AFBN should perform MCU to find out VUR and insist on prophylactic antibiotic until the VUR disappeared, patients with recurrent infection and serious VUR need urological treatment in order to prevent the formation of renal scar.

Background
Urinary tract infection includes upper urinary tract infection (UUTI)and lower urinary tract infection(LUTI) according to the location infected, the treatment and prognosis of UUTI and LUTI are quite different.AFBN is a kind of serious UUTI,and even worse than acute pyelonephritis (APN),The patients who have AFBN are almost infants and young children,AFBN can lead to renal scar and secondary hypertension, chronic renal failure.Vesicoureteral reflux (VUR) includes primary VUR and secondary VUR.Primary VUR is one of the pathogenic factors of AFBN and often exists in infancy stage [1].In this paper, we analyzed the clinical data of 11 infants cases with AFBN and VUR diagnosed and treated in our hospital in recent years retrospectively to improve the understanding of the two diseases.

Methods
Patients data Eleven infants with AFBN combined with VUR at Tianjin Children's Hospital from January 2017 to August 2019 were reported here. Table 1 shows the age,sex,symptom,urine culture and blood test and so on.There are 5 males and 6 females in this study,and the age is from 2 to 8 months,the median age is 5 months.The diagnostic criteria of AFBN were based on the results of renal computed tomography(CT) performed with contrast medium. The VUR diagnostic criteria is according to the five grades classification proposed by the international association of reflux nephropathy.The gold standard diagnosis is micturating cystourethrography (MCU), and the other urinary malformation diseases were excluded.
Clinical data and laboratory analysis the pathogenesis characteristics, family history and clinical manifestations of eleven infants were collected. Laboratory examination included urine routine, urine culture, C-reactive protein (CRP), blood neutrophil percentage (BNP), neutrophil-to-lymphocyte ratio (NLR).
Imaging examination methods: FHILPS Epiq5 color ultrasonic diagnostic instrument was used.CT examination used philips 256-row iCT scanner, followed by a three-phase dynamic enhanced scan, and iodine contrast medium was given at 1.5 ml/kg, arterial, venous and delayed scanning were followed after injection.SIMENS luminous select was used for MCU examination. After inserting the urine tube from the urethral orifice to the bladder, inject 76% meglumine diatrizoate contrast medium 40-80 ml by 1:4 according to the age, and then observe the reflux at bladder filling period and urination period.

Ethics
This study was approved by the medical ethics committee of Tianjin Children's hospital.All the guardians of the children gave consent to the study and signed informed consent.

Results
Clinical manifestations every patient had a fever,poor appetite, and had not irritative voiding symptoms,lethargy,vomiting,diarrhea or constipation. There was no family history of urinary malformation in 11 cases. (Table 1) Laboratory examination Table 1 shows that all urine routine tests were leukocyte urine, leucocyte count were from +/HP to 3+/HP.42 Urine culture were done and 34 samples were positive. The bacterial colony count was > 10 5 /mL, the positive rate was 80.95%.There were 19 gram-negative bacterias, 7 cases were Escherichia coli, 10 cases were pseudomonas aeruginosa, 1 case was klebsiella pneumoniae and 1 case was acinetobacter baumannii.There were 15 gram-positive bacterias, 11 cases were faecium, 3 cases were enterococcus faecalis and 1 case was enterococcus gallinarum .Blood CRP was from 25 mg/L to 200 mg/L.The percentage of neutrophils in blood was 52%-85%.The ratio of neutrophils to lymphocytes was 1.39-11.6.No abnormalities were found in the blood renal function tests, and all blood cultures were negative.
Imagign examination There were 4 infants infected in single kidney(3 infants in left and 1 in right) and 7 infants infected in both kidneys; 10 infants had left VUR (1 case of grade I, 2 cases of grade II, 2 cases of grade III, 3 cases of grade IV and 2 cases of grade V).9 infants had right VUR(4 cases of grade II, 2 cases of grade III, 1 case of grade IV, 2 cases of grade V). results of 10 cases showed abnormalities in the first b-ultrasound examination, which showed different degrees of renal pelvis dilation, ureter dilatation and hydronephrosis.CT scan and enhancement of the kidney showed that the lesion was in different degrees of decreased wedge perfusion.MCU showed unilateral or bilateral VUR and the grade was from I to V( Table 2, Fig. 1,2

,3,4)
Therapy and follow-up Before any antibiotic therapy was started,urine specimen should be obtained for urine culture. Antibiotic treatment is emergency to eradicate the infection. Antibiotic was given for 10-14 days according to the drug susceptible test,when MCU examination showed VUR, followed by daily low dose antibiotics taken at night. MCU examination was arranged after infection controlled within 2-4 weeks.Only 3 infants'parents agreed to MCU examination and insisted on antibiotic prophylaxis at the first infection. Febril UTI was repeated 1-3 times in other 8 cases within the follow 4-9 months.Then they had the MCU examination which showed VUR, and insisted on antibiotic prophylaxis.Two infants haven't recurrent infection since we followed up for 3-5 months long.The other 9 infants were followed up for 11-39 months, and 7 infants stopped the daily low dose antibiotics by themselves ,then they had the febrile urinary tract infection 1-3 times .Two patients still had febrile urinary tract infection during the daily low dose antibiotics therapy and were transferred to surgical correction, one infant had Cohen operation, and another infant had the dextranomer/hyaluronic acid(DxHA) injection treatment. No recurrent infection occurred after surgical treatment. (Table 1)   ( Fig. 1A,1B  DSMA.Some researchers report that AFBN happens at any age stages, but the incidence of infants is higher than others, 30% infants from 6 to 12 months with AFBN would recurrent after the first infection [5].The younger they are,the higher danger of recurrence is. VUR is the first reason for AFBN recurrence,the other reasons include bladder and bowel dysfuction (BBD), age, race, etc. When VUR and BBD exist at the same time, the risk is higher [6].In this study every paitent is less than 1 year old, which was consistent with literature reports. There was not defecation abnormalities or urinary abnormalities family history, It is necessary to increase the sample numbers to observe the relationship between the two factors and AFBN recurrence.
Since AFBN can cause renal scarring, it is necessary to find the presence of VUR or other malformations after the diagnosis of AFBN to determine how to prevent recurrence.Imaging studies are performed for UTI localization, urological malformation, renal scarring, and renal function evaluation.Imaging diagnosis includes B ultrasound, MCU ,CT and DMSA [7].Some studies found that renal enhanced CT examination also has a high specificity and sensitivity for the diagnosis of AFBN [8,9],Due to the absence of DMSA instrument in our hospital, 11 infants in this group had renal enhanced CT examination, and the lesion area had multiple wedge-shaped decreased perfusion area. The most infants with AFBN did not complained backache or kidney area taps pain because of the age, If they have a high fever (T 39 ° C or higher), renal ultrasound abnormality ,urine bacterias infection except E.coli ities, blood neutrophils ratio > 60% or CRP > 40 mg/L, which are the most possible predictions of renal scarring [10].A study on 2-month-infant with AFBN and VUR showed that when the VUR grade is III -V, the percentage of peripheral blood neutrophils (BNP),The ratio of neutrophils to lymphocytes (NLR) was significantly higher than that of patients with VUR grade I-III [11].In this study, blood CRP 25 mg/L-200 mg/L,The percentage of neutrophils in blood was 52%-85%.The ratio between neutrophils and lymphocytes was 1.39-11.6, which was consistent with the reported literature.
Renal scarring is one of the causes of chronic renal failure, risk factors of renal scarring include the III-V grade VUR. Febrile UTI keeping on 2 days and the recurrence UTI [12],animal experiments showed that in the first seven days of infection, rapid and effective treatment can prevent renal scarring, early appropriate treatment can reduce the damage of kidney,It is a consensus that choose the antibiotic according to the results of urine culture and drug susceptibility test [13,14,15]. low dose antibiotic prophylaxis in girls with VUR or BBD has good curative effect,which did not reduce the occurrence of febril UTI in patients with III-V grade VUR.The risk in prevention treatment group is even higher than control group, the reason may be associated with antibiotics increased bacterial drug resistance [18]. 9 cases in this article do not have UTI again since they insist on using antibiotic prophylaxis.
Studies showed that DxHA endoscopic injection is a method to solve VUR.The success rate is 79% in II grade, 72% in III grade, 63% in IV grade, 51% in V grade, the success rate is not high and the effect is not lasting. [19,20]There was no significant difference between endoscopic intradermal injection and antibiotic prophylaxis in reducing urinary tract infection recurrence and renal scar formation, but endoscopic treatment reduced recurrent febrile urinary tract infection. [21]A study of repeating MCU on 18.9% patients who have one or more times febril UTI after surgery found that VUR were still exist in 48.8% patients, then researchers summarized the risk factors in these febril UTI patients recurrence include Cystitis cystitis was present at injection, renal scar existing before surgery, the implant disappeared found by B ultrasonic examination after 3 months follow-up. [22]In this study, only one patient received this treatment in another hospital, and there was no recurrence in 5 months follow-up.An other case had cohen operation because of severe reflux.These two patients did not have the febril UTI when they stop the antibiotic prophylaxis after operation. The prognosis of three kinds treatment is different ,Some scholars reported that the recurrence rate after antibiotic prophylaxis was 12%-36%, the recurrence rate after surgical reimplantation was 4.6-24%, and the recurrence rate after endoscopic treatment was 0.75-27% [23,24], it suggests that the treatment plan for patients with VUR should be discussed by nephrology and urology doctors.

Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The work was approved by the Tianjin Chlidren's Hospital Ethics Committee and inforemed consent was obtained from all subjects.

Consent for publication
Written informed consent will be taken from all participants before their taking part in the study.

Availability of data and materials
All data generated or analysed during this study are included in this article [symptom,laboratory tset data,and so on].

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by the Program of Tianjin Science and Technology Plan(No.18ZXDBSY00170), The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Authors' contributions
YL is first author who wrote the first draft of the manuscript and contributed to the design of the study; WHW performed the literature research;JC and DL performed the imaging pictures,CQC refined the protocol and the principal investigators of this study;All authors revised the protocol critically for important intellectual content and approved the final manuscript.

Acknowledgements
Thanks for aiding supported by imaging department of Tianjin Children's Hospital.  Figure 1 case 3 1A Multiple irregular lamellar hypperfusion areas were observed in the left renal parenchyma and no abnormal density shadow was observed in the right renal parenchyma.

Figures
1B After 3 monoths,multiple irregular lamellar hypoperfusion areas were observed in the left renal parenchyma in CT enhancement and the scope was smaller than before. 1C Contrast medium refluxed from bladder to bilateral ureter and renal pelvis, left ureter, renal pelvis and calyces dilated, right ureter and calyces had not significantly dilated.      After 1 year,repeated the MCU during urination, contrast-medium flow into the right renal pelvis, the renal pelvis and calices were slightly dilated, ureter was not dilated, and no reflux was found at the left. After 1 year,repeated the MCU during urination, contrast-medium flow into the right renal pelvis, the renal pelvis and calices were slightly dilated, ureter was not dilated, and no reflux was found at the left.