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.

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.

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.

Antimicrobial prophylaxis for children with vesicoureteral reflux.

BACKGROUND: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.).

Pharmacologic Treatment of Pediatric Hypertension.

Prevalence of hypertension is increasing in children and adolescents. Uncontrolled hypertension in children not only causes end organ damage but also increases the risk of adult hypertension and cardiovascular disease. Clinical trials have proven efficacy of antihypertensive medications in children. These medications are well tolerated by children with acceptable safety profile. The choice of agent is usually driven by underlying etiology of hypertension, profile of its side effects, and clinician's preference. This article will review currently available pediatric data on mechanism of action, common adverse effects, pediatric indication, recent clinical trial, and newer drugs in the common classes of antihypertensive medications.

Atypical hemolytic uremic syndrome: a clinical conundrum.

BACKGROUND: Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. However, STEC identification is limited by the natural history of HUS. METHODS: The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S). A single-center retrospective review (2003-2012) of 42 HUS patients (follow-up 31.3 ± 38.7 months) was carried out. HUS was managed clinically with supportive treatments such as dialysis, plasma therapy, and eculizumab. RESULTS: There was no significant difference in the D+S+ (31 %), D+S- (50 %) and D-S- (19 %) groups in the outcome variables of chronic kidney disease stages I-II (100 % vs 81 % vs 67 %) and proteinuria at follow-up (20 % vs 12.5 % vs 33.3 %), hospitalization duration (16.0 ± 8.7 vs 18.1 ± 9.5 vs 23.7 ± 12.9 days); dialysis requirement (50 % vs 81 % vs 66.7 %), and dialysis duration (10.2 ± 1.9 vs 33.3 ± 72.8 vs 10.3 ± 8.1 days). There was no significant difference in study outcomes in STEC+ (59 %) versus STEC- (41 %) groups. Genetic testing was performed in 12 % of HUS patients based on age, recurrent HUS, familial HUS, persistently low C3, or prolonged dialysis, and 80 % of the patients tested were positive for genetic mutations. CONCLUSIONS: Our study does not show poorer outcomes in STEC- HUS. Indications and the cost-effectiveness of genetic testing, eculizumab, and plasmapheresis in STEC- HUS need to be evaluated further.

Utility of sedation for young children undergoing dimercaptosuccinic acid renal scans.

BACKGROUND: No studies have examined whether use of sedation during a Tc-99 m dimercaptosuccinic acid (DMSA) renal scan reduces patient discomfort. OBJECTIVE: To compare discomfort level during a DMSA scan to the discomfort level during other frequently performed uroradiologic tests, and to determine whether use of sedation during a DMSA scan modifies the level of discomfort. MATERIALS AND METHODS: We examined the discomfort level in 798 children enrolled in the Randomized Intervention for children with Vesicoureteral Reflux (RIVUR) and Careful Urinary Tract Infection Evaluation (CUTIE) studies by asking parents to rate their child's discomfort level with each procedure on a scale from 0 to 10. We compared discomfort during the DMSA scan and the DMSA image quality between centers in which sedation was used >90% of the time (sedation centers), centers in which sedation was used <10% of the time (non-sedation centers), and centers in which sedation was used on a case-by-case basis (selective centers). RESULTS: Mean discomfort level was highest for voiding cystourethrogram (6.4), followed by DMSA (4.0), followed by ultrasound (2.4; P<0.0001). Mean discomfort level during the DMSA scan was significantly higher at non-sedation centers than at selective centers (P<0.001). No difference was apparent in discomfort level during the DMSA scan between sedation centers and selective centers (P=0.12), or between the sedation centers and non-sedation centers (P=0.80). There were no differences in the proportion with uninterpretable DMSA scans according to sedation use. CONCLUSION: Selective use of sedation in children 12-36 months of age can reduce the discomfort level experienced during a DMSA scan.

The RIVUR trial: a factual interpretation of our data.

Vesicoureteral reflux (VUR) increases the risk of urinary tract infection (UTI) and renal scarring. Many prospective studies have evaluated the role of antimicrobial prophylaxis in the prevention of recurrent UTI and renal scarring in children with VUR. Of these, the RIVUR trial was the largest, randomized, placebo-controlled, double blind, multicenter study, involving 607 children aged 2-72 months with grade I-IV VUR and a first or second symptomatic UTI. The median age of children in the RIVUR trial was 12 months, 92% were female, 91% were randomized after a first UTI, 86% had a febrile index UTI, and 71 (56%) of 126 toilet-trained children had bladder bowel dysfunction. Trimethoprim/sulfamethoxazole reduced the risk of UTI recurrences by 50% (hazard ratio 0.50; 95% confidence interval 0.34-0.74) as compared to placebo. No significant difference was seen in renal scarring between the two groups. However, this does not invalidate the role of prophylaxis in preventing renal scars because RIVUR and other recent prospective studies were not designed to address renal scarring as a primary study endpoint. In view of the RIVUR Trial and other studies that showed similar results, albeit in selected groups of patients, the debate on antimicrobial prophylaxis should shift from "no prophylaxis" to "selective prophylaxis" in children with VUR.

Pediatric hypertensive emergencies.

Hypertensive emergency is a life-threatening condition that requires immediate evaluation and treatment. In children, severe hypertension can be caused by a variety of different underlying conditions. It usually presents with neurological involvement; however, signs and symptoms of injury to the kidneys, myocardium and eyes can also be present. Hospitalization for intravenous treatment with antihypertensive(s) and close monitoring in an intensive care setting are required for these patients. Few studies in children with hypertensive emergency have been done in the last several years. The findings and observations of these studies are discussed in this review.

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.

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.

The impact of change in volume and left-ventricular hypertrophy on left-ventricular mechanical dyssynchrony in children with end-stage renal disease.

Left-ventricular dyssynchrony (LVD) adversely affects systolic performance and has not been previously evaluated in children with end-stage renal disease (ESRD). We hypothesized (1) that LVD in children with ESRD would be significantly increased compared with controls and (2) that volume load and left-ventricular hypertrophy (LVH) would be associated with increased LVD. This was a prospective observational study in which real-time three-dimensional echocardiographic data were acquired in 27 stable children with ESRD (13 peritoneal dialysis [PD] and 14 hemodialysis [HD]) and 29 normal controls. Data were acquired before and after an HD session. Dyssynchrony index (SDI) was defined per standard formulae and was normalized to cardiac cycle duration (SDIp). Left-ventricular mass (LVM) was obtained from M-mode echocardiography and was normalized to height(2.7) (LVM index). The mean age (13.8 vs. 11.3 years) and SDI, SDIp, LVM, and LVM index were significantly greater among children with ESRD than among controls (p < 0.05). Demographics and heart rates were comparable between HD and PD subgroups, whereas SDI 16 and 12 segments, SDIp 16 segments, and LVM were significantly greater in the HD group. SDI and SDIp 16 segments improved after an HD session (p < 0.05); LVM and LVM index remained unchanged. LVD was significantly greater in patients with LVH compared with those without LVH. Children with ESRD had significant LVD and increased LVM compared with controls. Increased LVD in those undergoing HD rather than PD, as well as the improvement in synchrony after HD, suggest that volume may modulate LVD. LVD was increased in children with LVH. LVD in children with ESRD may have pathogenic implications.

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.

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.

Managing urinary tract infections.

Urinary tract infections (UTI) are common in childhood. Presence of pyuria and bacteriuria in an appropriately collected urine sample are diagnostic of UTI. The risk of UTI is increased with an underlying urological abnormality such as vesicoureteral reflux, constipation, and voiding dysfunction. Patients with acute pyelonephritis are at risk of renal scarring and subsequent complications such as hypertension, proteinuria with and without FSGS, pregnancy-related complications and even end-stage renal failure. The relevance and the sequence of the renal imaging following initial UTI, and the role of antimicrobial prophylaxis and surgical intervention are currently undergoing an intense debate. Prompt treatment of UTI and appropriate follow-up of those at increased risk of recurrence and/or renal scarring are important.

Iron deficiency in children with early chronic kidney disease.

Iron deficiency (ID) contributes to the development of anemia in patients with chronic kidney disease (CKD). The frequency of ID in children with early CKD has not previously been reported. This was a retrospective chart review of children with CKD stages 2 and 3 followed at the CKD clinic of Children's Hospital of Michigan. ID was defined as low ferritin and transferrin saturation <20%. Patients on iron supplements were considered as iron-deficient cases. There were 50 patients included in the study (72% male) with a mean age of 10.31 (±5.21). The mean glomerular filtration rate (GFR) was 55.4 ml/min/1.73 m(2) (±14.61). ID was present in 42% of patients, out of whom almost half (42.9%) presented with anemia. Females had a higher frequency of ID (64.3%). The frequency of ID with anemia increased from 4.3% to 29.6%, (p = 0.03) in stage 2 to stage 3 CKD, respectively. The frequency of ID without anemia also increased with progression of CKD from stage 2 to stage 3, however, the difference was not statistically significant. ID is frequent in patients with early CKD. Monitoring of iron tests and treatment of ID is important in this population of patients.