Biomarkers for urinary tract infection: present and future perspectives.

A prompt diagnosis of urinary tract infection (UTI) is necessary to minimize its symptoms and limit sequelae. The current UTI screening by urine test strip analysis and microscopic examination has suboptimal diagnostic accuracy. A definitive diagnosis of UTI by urine culture takes two to three days for the results. These limitations necessitate a need for better biomarkers for the diagnosis and subsequent management of UTI in children. Here, we review the value of currently available UTI biomarkers and highlight the potential of emerging biomarkers that can facilitate a more rapid and accurate UTI diagnosis. Of the newer UTI biomarkers, the most promising are blood procalcitonin (PCT) and urinary neutrophil gelatinase-associated lipocalin (NGAL). PCT can provide diagnostic benefits and should be considered in patients who have a blood test for other reasons. NGAL, which is on the threshold of clinical care, needs more research to address its scope and utilization, including point-of-care application. Employment of these and other biomarkers may ultimately improve UTI diagnosis, guide UTI therapy, reduce antibiotic use, and mitigate UTI complications.

Body water percentage from childhood to old age.

BACKGROUND: Total body water (TBW) increases with growth, but the body water percentage (TBW%) decreases with aging. The objective of our study was to delineate TBW% in males and females by bioelectrical impedance analysis (BIA) from early childhood to old age. METHODS: We enrolled 545 participants aged 3 to 98 years (258 male, 287 female). Among the participants, 256 had a normal weight and 289 were overweight. The TBW was measured by BIA, and TBW% was derived by dividing the TBW (L) value by body weight (kg). For analysis, we divided participants into the four age groups of 3-10, 11-20, 21-60, and ≥61 years. RESULTS: In normal-weight subjects, the TBW% was similar at 62% between males and females in the 3-10-year group. It remained unchanged in males until and through adult life, then decreased to 57% in the ≥61-year group. In normal-weight female subjects, the TBW% decreased to 55% in the 11-20-year group, remained relatively unaltered in the 21-60-year group, then decreased to 50% in the ≥61-year group. In overweight subjects, the TBW% values in males, as well as females, were significantly lower as compared to those with normal weight. CONCLUSION: Our study showed that the TBW% in normal-weight males changes very little from early childhood to adult life compared to that of females, who showed a decrease in TBW% during the pubertal years. In normal-weight subjects of both sexes, the TBW% decreased after the age of 60 years. Overweight subjects had significantly lower TBW% as compared to those with normal weight.

A new prediction model for total body water estimation by BIA in children with normal and excessive weight.

BACKGROUND: Various methods, including bioelectrical impedance analysis (BIA), are used for total body water (TBW) estimation. The objective of our study by BIA was to develop a new predication model based on corrected TBW for normal adult BMI, a concept similar to the standardization of glomerular filtration rate by relating it to the average adult body surface area. METHOD: We measured TBW by BIA in 335 children 3-21 years old with normal or excessive body weight. Based on our data, we derived a new prediction model for TBW (L) for females {[(72.784 + 0.4093 × weight)∗Corrected TBW]/100} and males {[(57.944 + 0.6551 × weight)∗Corrected TBW]/100}. For validation, we compared our prediction model with three other models on TBW by BIA and dilution methods. RESULTS: Our model's error size to predict TBW showed lower cross-validated root mean square error (CV-RMSE) as compared to three other models versus our dataset by BIA and two other datasets by dilution methods. Our model also showed a smaller error (2.059) in CV-RMSE as compared to other models by dilution methods (2.126, 2.873, and 4.384) for normal and excessive weight combined. This implies that our model is more robust when excessive weight individuals are included in the data.. CONCLUSION: Our prediction model for TBW estimation by BIA performs better as compared to some other models based on BIA and dilution method datasets. Furthermore, our prediction model is the only one that is devised to be applicable to children and young adults with both normal as well as excessive weight.

Duration of initial prednisolone therapy for first episode of childhood nephrotic syndrome based on time to response.

Background: The duration of initial corticosteroid therapy in newly diagnosed Idiopathic nephrotic syndrome (INS) is about 3 months. Our study was designed to test the feasibility of a shorter duration of corticosteroid therapy in newly diagnosed INS who show a quicker response. Methods: Patients who responded within 10 days (Group A) received 8 weeks of corticosteroid therapy as compared to 12-14 weeks of standard therapy in those who responded between >10 days to 28 days (Group B), and follow up for 52 weeks. The primary endpoint is time to first relapse after treatment completion. (NCT03878914, March 18, 2019). Results: A total of 33 children with INS were enrolled and the follow-up data were analyzed. The clinical and laboratory characteristics of patients in both groups were similar. No significant difference was found in time to first relapse [65(14.5, 159) days for Group A vs. 28(17, 61.5) days for Group B, P = 0.371], the incidence of frequently relapsing nephrotic syndrome [6/18 (33.3%) vs. 5/10(50%), P = 0.644] or requirement for alternative immunosuppressant [4/18 (22.2%) vs. 1/10 (10%), P = 0.769]. Group A received similar corticosteroid dose compare with Group B (3511 ± 2421 mg/m2 vs. 4117 ± 2556 mg/m2, P = 0.524). Frequency and severity of corticosteroid-related complications was similar in both groups. Conclusions: The time to first relapse and the number of relapses per patient were comparable between the two groups. However, more patients in Group A relapsed and the mean total dose of prednisolone for the study period was very similar between the two groups.

Clinical presentation and management of nephrotic syndrome in the first year of life: A report from the Pediatric Nephrology Research Consortium.

Background and objectives: Nephrotic syndrome (NS) in the first year of life is called congenital (CNS) if diagnosed between 0-3 months, or infantile (INS) if diagnosed between 3-12 months of age. The aim of this study was to determine if there were clinically meaningful differences between CNS and INS patients, regarding clinical presentation, management and outcomes. Design setting participants and measurements: Eleven Pediatric Nephrology Research Consortium sites participated in the study, using IRB-approved retrospective chart reviews of CNS and INS patients born between 1998 and 2019. Data were collected on patient characteristics, pertinent laboratory tests, provided therapy, timing of unilateral/bilateral nephrectomy and initiation of renal replacement therapy (RRT). Results: The study included 69 patients, 49 with CNS and 20 with INS, with a median age at diagnosis of 1 and 6 months, respectively. Management for the two groups was similar regarding nutrition, thyroxin supplementation, immunoglobulin administration, and thrombosis prophylaxis. Within the first 2 months after diagnosis, daily albumin infusions were used more often in CNS vs. INS patients (79 vs. 30%; p = 0.006), while weekly infusions were more common in INS patients (INS vs. CNS: 50 vs. 3%; p = 0.001). During the 6 months preceding RRT, albumin infusions were more frequently prescribed in CNS vs. INS (51 vs. 15%; p = 0.007). Nephrectomy was performed more often in CNS (78%) than in INS (50%; p = 0.02). End-stage kidney disease tended to be more common in children with CNS (80%) vs. INS (60%; p = 0.09). Conclusion: Compared to INS, patients with CNS had a more severe disease course, requiring more frequent albumin infusions, and earlier nephrectomy and RRT. Despite center-specific variations in patient care, 20-40% of these patients did not require nephrectomy or RRT.

Kidney Echogenicity and Vesicoureteral Reflux in Children with Febrile Urinary Tract Infection.

OBJECTIVE: To evaluate increased kidney echogenicity as a predictor of vesicoureteral reflux (VUR) in young children with first febrile urinary tract infection (UTI). STUDY DESIGN: We performed a single center retrospective study of hospitalized children with first febrile UTI diagnosed in accordance with the American Academy of Pediatrics guidelines. All patients had kidney bladder ultrasound (KBUS) and voiding cystourethrography. Variables analyzed using χ2 test or Mann-Whitney U test as appropriate. Multivariable logistic regression analysis was performed for the abnormal KBUS findings and OR and 95% CI were calculated. RESULTS: Our cohort included 415 children (830 kidney units) with median age of 5 months (1 month to 5 years) and 80% were female. One hundred thirty-two (31.8%) patients had abnormal KBUS, including increased echogenicity in 45 patients. Overall, 42.2% of patients with increased echogenicity had VUR vs 23.3% with normal ultrasound (P = .013) and 31.1% of patients with increased echogenicity had high-grade III-V VUR vs 8.1% with normal ultrasound (P = .001). In total, 24.3% of kidneys with increased echogenicity had VUR vs 20% with normal ultrasound (P = .246) and 20% of kidneys with increased echogenicity had high-grade III-V VUR vs 9.9%with normal ultrasound (P = .005). CONCLUSIONS: These data support adding increased kidney echogenicity to the list of other KBUS findings that are helpful in decision making about a need for voiding cystourethrography in young children with first febrile UTI.

Current Understanding of Nephrotic Syndrome in Children.

Nephrotic syndrome in children is mostly idiopathic in origin. About 90% of patients respond to corticosteroids; 80-90% have at least one relapse and 3-10% become corticosteroid resistant after the initial response. A kidney biopsy is seldom indicated for diagnosis except in patients with atypical presentation or corticosteroid resistance. For those in remission, the risk of relapse is reduced by the administration of daily low dose corticosteroids for 5-7 days at the onset of an upper respiratory infection. Some patients may continue having relapses through adult life. Many country-specific practice guidelines have been published, which are very similar with clinically insignificant differences.

Primary Vesicoureteral Reflux and Renal Scarring.

Vesicoureteral reflux (VUR) is the commonest congenital anomaly of urinary tract in children. It is mostly diagnosed after a urinary tract infection or during evaluation for congenital anomalies of the kidney and urinary tract. High-grade VUR, recurrent pyelonephritis, and delayed initiation of antibiotic treatment are important risk factors for renal scarring. The management of VUR depends on multiple factors and may include surveillance only or antimicrobial prophylaxis; very few patients with VUR need surgical correction. Patients with renal scarring should be monitored for hypertension and those with significant scarring should also be monitored for proteinuria and chronic kidney disease.

Calcineurin inhibitors and renal biopsy in children with idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (NS) is common in children, and most patients respond to corticosteroid therapy. Patients who relapse may need additional immunosuppression with cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (CNI), or rituximab. Many such patients undergo protocol renal biopsies before and after the initiation of CNI therapy. The main objective of our study was to assess the role of protocol renal biopsies in the monitoring of CNI-induced nephrotoxicity in patients with steroid-dependent (SD)/frequent relapse (FR) NS. We did an Institutional Review Board (IRB)-approved retrospective chart review of patients who were diagnosed with NS at the Children's Hospital of Michigan from January 2000 to June 2019. Study inclusion criteria were a diagnosis of NS, age 1 - 21 years at initial diagnosis, SD/FR clinical course, patients with initial steroid resistance with renal biopsy showing minimal change disease, and renal biopsy before and after CNI initiation. The data is presented on 24 patients who met study inclusion criteria. Only 3 patients (12.5%) showed evidence of chronic CNI nephrotoxicity after a median treatment 66.5 months (range 12 - 153 months). Our study revealed that a baseline renal biopsy before starting CNI therapy for children with FR/SDNS is not necessary. A renal biopsy may be considered after 2 - 3 years of CNI administration in selected few cases in whom the diagnosis of CNI nephrotoxicity might help change the management.

Contemporary Management of Urinary Tract Infection in Children.

Urinary tract infection (UTI) is common in children, and girls are at a significantly higher risk, as compared to boys, except in early infancy. Most cases are caused by Escherichia coli Collection of an uncontaminated urine specimen is essential for accurate diagnosis. Oral antibiotic therapy for 7 to 10 days is adequate for uncomplicated cases that respond well to the treatment. A renal ultrasound examination is advised in all young children with first febrile UTI and in older children with recurrent UTI. Most children with first febrile UTI do not need a voiding cystourethrogram; it may be considered after the first UTI in children with abnormal renal and bladder ultrasound examination or a UTI caused by atypical pathogen, complex clinical course, or known renal scarring. Long-term antibiotic prophylaxis is used selectively in high-risk patients. Few patients diagnosed with vesicoureteral reflux after a UTI need surgical correction. The most consequential long-term complication of acute pyelonephritis is renal scarring, which may increase the risk of hypertension or chronic kidney disease later in life. Treatment of acute pyelonephritis with an appropriate antibiotic within 48 hours of fever onset and prevention of recurrent UTI lowers the risk of renal scarring. Pathogens causing UTI are increasingly becoming resistant to commonly used antibiotics, and their indiscriminate use in doubtful cases of UTI must be discouraged.

Total body water by BIA in children and young adults with normal and excessive weight.

BACKGROUND: Estimation of total body water (TBW) is essential for clinical care. OBJECTIVE: Evaluation of changes in TBW by bioelectrical impedance analysis (BIA) in children and young adults with excessive weight. DESIGN: Data was collected in individuals aged 3-21 years with normal (n = 202) or excessive body weight (n = 133). The BIA results from individuals with normal weight were compared with two previously published studies in children by isotope dilution methods. RESULTS: Individuals with excessive weight had a higher mean TBW (27.87 L, SE 0.368) for height and age as compared to individuals with normal weight (23.95 L, SE 0.298), P<0.001. However, individuals with excessive weight had lower mean TBW (24.93 L, SE 0.37) for weight and body surface area (BSA) as compared to individuals with normal weight (26.94 L, SE 0.287), P<0.001. Comparison with two previously published studies showed no significant differences in mean TBW with one ((p = 1.00) but a significant difference with another study (p = 0.001). CONCLUSIONS: Individuals with excessive weight had 16.5% higher mean TBW for height and age and 7.4% lower TBW for weight and BSA as compared to normal weight individuals. Our study validates the feasibility of data collection in pediatric outpatient setting by BIA.

Laboratory Findings After Urinary Tract Infection and Antimicrobial Prophylaxis in Children With Vesicoureteral Reflux.

It is a common practice to monitor blood tests in patients receiving long-term trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis for recurrent urinary tract infections. This multicenter, randomized, placebo-controlled trial enrolled 607 children aged 2 to 71 months with vesicoureteral reflux diagnosed after symptomatic urinary tract infection. Study participants received TMP-SMZ (n = 302) or placebo (n = 305) and were followed for 2 years. Serum electrolytes (n ≥ 370), creatinine (n = 310), and complete blood counts (n ≥ 206) were measured at study entry and at the 24-month study conclusion. We found no significant electrolyte, renal, or hematologic abnormalities when comparing the treatment and placebo groups. We observed changes in several laboratory parameters in both treatment and placebo groups as would normally be expected with physiologic maturation. Changes were within the normal range for age. Long-term use of TMP-SMX had no treatment effect on complete blood count, serum electrolytes, or creatinine. Our findings do not support routine monitoring of these laboratory tests in children receiving long-term TMP-SMZ prophylaxis.

Cost-Utility of Antimicrobial Prophylaxis for Treatment of Children With Vesicoureteral Reflux.

Objective: Antimicrobial prophylaxis for children with vesicoureteral reflux (VUR) reduces recurrences of urinary tract infection (UTI) but requires daily antimicrobials for extended periods. We used a cost-utility model to evaluate whether the benefits of antimicrobial prophylaxis outweigh its risks and, if so, to investigate whether the benefits and risks vary according to grade of VUR. Methods: We compared the cost per quality-adjusted life-year (QALY) gained in four treatment strategies in children aged <6 years diagnosed with VUR after a first UTI, considering these treatment strategies: (1) prophylaxis for all children with VUR, (2) prophylaxis for children with Grade III or Grade IV VUR, (3) prophylaxis for children with Grade IV VUR, and (4) no prophylaxis. Costs and effectiveness were estimated over the patient's lifetime. We used $100,000/QALY gained as the threshold for considering a treatment strategy cost effective. Results: Based on current data and plausible ranges to account for data uncertainty, prophylaxis of children with Grades IV VUR costs $37,903 per QALY gained. Treating children with Grade III and IV VUR costs an additional $302,024 per QALY gained. Treating children with all grades of VUR costs an additional $339,740 per QALY gained. Conclusions: Treating children with Grades I, II, and III VUR with long-term antimicrobial prophylaxis costs substantially more than interventions typically considered economically reasonable. Prophylaxis in children with Grade IV VUR is cost effective.

Interobserver variability for interpretation of DMSA scans in the RIVUR trial.

INTRODUCTION: Technetium-99m dimercaptosuccinic acid (DMSA) renal scans are used in the diagnosis of renal scarring. In the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial that randomized 607 children, DMSA renal scans were used for evaluating the presence and the severity of renal scarring. OBJECTIVE: The aim was to determine interobserver variability in reporting of DMSA renal scans in the RIVUR trial. STUDY DESIGN: We compared DMSA renal scan reports for renal scarring and acute pyelonephritis from all non-reference local radiologists (ALRs) at study sites with adjudicated as well as non-adjudicated reports from two reference radiologists (RRs) of the RIVUR trial. Two-way comparisons of concordant and discrepant responses were analyzed using an unweighted kappa statistic between the ALR and the adjudicated RR interpretations. All analyses were performed using SAS v 9.4 (SAS institute 2015) and significance was determined at the 0.05 level. RESULTS: Of the 2872 kidneys evaluated, adjudicated RR reports had 119 (4%) kidneys with renal scarring compared with 212 (7%) by the ALRs. For 79% kidneys the grading for scarring reported by ALRs was either upgraded (24%) or downgraded (55%) by RRs. For acute pyelonephritis (n = 2924), adjudicated RR reports had 85 (3%) kidneys with pyelonephritis compared with 151 (5%) by the ALRs. For 85% kidneys, the grading for pyelonephritis reported by the ALRs was either upgraded (28%) or downgraded (57%) by the RRs. A three-way comparison revealed that all three (RR1, RR2, and ALR) agreed over presence of renal scarring in 19% cases and two of the three agreed in 80% cases. The respective numbers for pyelonephritis were 13% and 84%. The agreement rate for all DMSA scan reports between the RRs and the ALRs was 93%. DISCUSSION: The study revealed significant interobserver variability in the reporting of abnormal DMSA renal scans compared with the previously published studies. A noteworthy limitation was a lack of uniformity in local reporting of the scans. CONCLUSIONS: Our study highlights the need for optimizing the clinical yield of DMSA renal scans by more specific guidelines, particularly for standardized and uniform interpretation.

Variation in the level of detail in pediatric voiding cystourethrogram reports.

INTRODUCTION: Voiding cystourethrogram (VCUG) provides a wealth of data on urinary tract function and anatomy, but few standards exist for reporting VCUG findings. OBJECTIVE: We aimed to assess variability in VCUG reports and to test our hypothesis that VCUG reports from pediatric facilities and pediatric radiologists are more complete than those performed at other facilities or by non-pediatric radiologists. STUDY DESIGN: We analyzed original VCUG reports from children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. A 23-item checklist was created and used to evaluate reporting of technical (e.g. catheter size), anatomic (e.g. vesicoureteral reflux (VUR) presence and grade, bladder shape), and functional information (e.g. bladder emptying). Radiologists were classified as pediatric or non-pediatric radiologists. Facilities were categorized as to whether they were a free-standing pediatric hospital (FSPH), a pediatric "hospital within a hospital" (PHWH), a non-pediatric hospital (NPH), or an outpatient radiology facility (ORF). Multivariate linear regression was used to analyze factors associated with the completeness of the VCUG reports (percent of items reported from the 23-item checklist). RESULTS: Six-hundred and two VCUGs were performed at 90 institutions. Of those, 76% were read by a pediatric radiologist, and 49% were performed at a FSPH (Table). On average, less than half of the 23 items in our standardized assessment tool were included in VCUG reports (mean 48%, SD 12). The completeness of reports varied by facility type: 51% complete at FSPH (SD 11), 50% at PHWH (SD 10), 36% at NPH (SD 11), and 43% at ORF (SD 8) (p < 0.0001). In multivariate analysis, VCUG reports generated at NPH or ORF had 8% fewer items included (95% CI 3.0-12.8, p < 0.01), and those generated at PHWH did not differ from those generated at FSPH. Reports read by a non-pediatric radiologist had 6% fewer items included (95% CI 3-9.7; p < 0.01) compared with those read by a pediatric radiologist. DISCUSSION: There is substantial underreporting of findings in VCUG reports when assessing a widely represented sample of routine, community-generated reports using an idealized standard. Although VUR was often reported, other crucial anatomic and functional findings of the VCUG were consistently underreported across all facility types. CONCLUSION: Although pediatric radiologist and pediatric hospitals generated more complete VCUG reports compared with those having non-pediatric origins, the differences are small when considering the substantial underreporting of VCUG findings in general. This underscores the opportunities for improvement in reporting of VCUG findings.