Tej K. Mattoo

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial

OBJECTIVES. There has been intense discussion on the effectiveness of continuous antibiotic prophylaxis for children with vesicoureteral reflux, and randomized, controlled trials are still needed to determine the effectiveness of long-term antibiotics for the prevention of acute pyelonephritis. In this multicenter, open-label, randomized, controlled trial, we tested the effectiveness of antibiotic prophylaxis in preventing recurrence of pyelonephritis and avoiding new scars in a sample of children who were younger than 30 months and vesicoureteral reflux. METHODS. One hundred patients with vesicoureteral reflux (grade II, III, or IV) diagnosed with cystourethrography after a first episode of acute pyelonephritis were randomly assigned to receive antibiotic prophylaxis with sulfamethoxazole/trimethoprim or not for 2 years. The main outcome of the study was the recurrence of pyelonephritis during a follow-up period of 4 years. During follow-up, the patients were evaluated through repeated cystourethrographies, renal ultrasounds, and dimercaptosuccinic acid scans. RESULTS. The baseline characteristics in the 2 study groups were similar. There were no differences in the risk for having at least 1 pyelonephritis episode between the intervention and control groups. At the end of follow-up, the presence of renal scars was the same in children with and without antibiotic prophylaxis. CONCLUSIONS. Continuous antibiotic prophylaxis was ineffective in reducing the rate of pyelonephritis recurrence and the incidence of renal damage in children who were younger than 30 months and had vesicoureteral reflux grades II through IV.

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.

Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children

We evaluated the efficacy, safety, and dose–response relationship of fosinopril in children aged 6 to 16 years with hypertension or high-normal blood pressure with an associated medical condition requiring treatment. The study was a prospective, double-blind, placebo-controlled trial conducted in 78 clinical sites in the United States, Russia, and Israel. There were 4 phases: a screening phase of 10 days maximum, a 4-week dose–response phase, a placebo withdrawal phase of 2 weeks maximum, and a 52-week open-label safety phase. The primary objective of the dose–response phase was to determine whether low (0.1 mg/kg), medium (0.3 mg/kg), or high (0.6 mg/kg) doses of fosinopril based on established adult dosing affect trough seated systolic blood pressure. During the dose–response phase, all 3 doses were equally effective in lowering systolic blood pressure. During the placebo withdrawal phase, there was an adjusted mean systolic blood pressure increase of 5.2 mm Hg for the placebo group and 1.5 mm Hg for the fosinopril group, a net withdrawal effect of 3.7 mm Hg (P=0.013). Fosinopril was well tolerated; serious adverse events occurred infrequently and were generally not attributed to fosinopril. Because children appear to be more sensitive to lower doses of fosinopril than adults, starting doses for children should be ≤0.1 mg/kg.

Vesicoureteral Reflux and Reflux Nephropathy

Primary vesicoureteral reflux (VUR) is the commonest congenital urological abnormality in children, which has been associated with an increased risk of urinary tract infection (UTI) and renal scarring, also called reflux nephropathy (RN). In children, RN is diagnosed mostly after UTI (acquired RN) or during follow-up for antenatally diagnosed hydronephrosis with no prior UTI (congenital RN). The acquired RN is more common in female children, whereas the congenital RN is more common in male children. This observation in children might help explain the differences in the clinical presentation of RN in adults, with males presenting mostly with hypertension, proteinuria, and progressive renal failure as compared with females who present mostly with recurrent UTI and have a better outcome. Known risk factors for RN include the severity of VUR, recurrent UTI, and bladder-bowel dysfunction; younger age and delay in treatment of UTI are believed to be other risk factors. Management of VUR is controversial and includes antimicrobial prophylaxis, surgical intervention, or surveillance only. No evidence-based guidelines exist for appropriate follow-up of patients with RN.

The RIVUR Trial: Profile and Baseline Clinical Associations of Children With Vesicoureteral Reflux

BACKGROUND AND OBJECTIVE: Vesicoureteral reflux (VUR) is diagnosed in ∼30% to 40% of children who have imaging studies after urinary tract infections (UTIs). Our goal is to characterize children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial and to compare our study cohort with those from previously published studies. METHODS: RIVUR investigators from 19 pediatric sites in the United States recruited 607 children with grade I through IV VUR. Children were enrolled after a first or second UTI. This cross-sectional report of baseline data includes extensive clinical, parental report, and imaging study results. RESULTS: RIVUR recruited 607 children (558 girls, 49 boys) with grade I (11%), II (42%), III (38%), or IV (8%) reflux. The median age was 12 months, and most children (91%) were enrolled after their first UTI. The UTI leading to enrollment was both febrile and symptomatic for 323 children, febrile only in 197 children, and symptomatic only in 86. Renal involvement at baseline as documented by a 99mTc dimercaptosuccinic acid scan was uncommon with cortical defects identified in 89 (15%) children. Bladder and bowel dysfunction was identified in 71 (56%) of 126 toilet-trained subjects assessed. CONCLUSIONS: RIVUR is the largest prospective, randomized trial for children with primary VUR to date, comparing prophylaxis with placebo. The study sample comprises patients from 19 pediatric clinical sites in the United States, whose demographic and clinical characteristics may differ from those of children enrolled in previous trials from other countries.

Measurement of Blood Pressure in Children: Recommendations and Perceptions on Cuff Selection

Objectives. To review some of the recent recommendations on blood pressure (BP) cuff selection, including those by the Task Force and its update, and to survey the perceptions on cuff selection among practitioners. Methods. The study was conducted in two parts. In the first, we selected three brands of commonly used infant, child/pediatric, small adult, adult, and large adult BP cuffs. From the median width of each, we derived the required upper arm length (UAL) for the cuff to cover three quarters or two thirds of the UAL, and with the help of a published normal UAL at various ages, we matched the derived UAL with the corresponding age at the 50th percentile. Similarly, we derived the midupper arm circumference (UAC) so that the available cuffs would cover 40% of the UAC, and by using the published normal UAC at various ages, we matched the derived UAC with the corresponding age at the 50th percentile. The second part of the study involved a survey by multiple choice questionnaire mailed to 400 hospital- and office-based pediatricians, residents, and nurses at the Childrens Hospital of Michigan. Included in the survey were questions about the age at which practitioners would choose the cuffs described above; the minimum age they would consider using an adult cuff in a pediatric patient with an average height and weight; selecting a cuff using UAL as a criterion; selecting a large versus a small cuff when the appropriate cuff size is not available; and the Task Force definition of hypertension. Results. Using three quarters of the UAL as a criterion, it seems that a large adult cuff should be appropriate for an average-size 6-year-old child and that using two thirds of UAL as a criterion, the cuff should be appropriate for an average-size 7- to 8-year-old child. Similarly, by using 40% of the mid-UAC as a criterion, an adult cuff would be of no use in an average pediatric patient at any age. Our survey revealed that 57% of practitioners would consider using a neonatal cuff for patients up to 1 month of age, 65% would use an infant cuff for those 1 year of age, 49% would use a child/pediatric cuff for those 5 years of age, and 84% would use a small adult cuff for those 10 years of age and older. Most (83%) of the practitioners would consider using an adult cuff in children 11 years of age and older. Practitioners are likely to use a smaller cuff than is appropriate by two thirds or three quarters of UAL criteria, and a larger cuff than is appropriate, particularly in older children, by 40% of UAC criteria. Using UAL as a criterion, a majority (59%) of practitioners use cuffs that cover two thirds of the distance between the axilla and the cubital fossa. Ninety-two percent of practitioners believe that a smaller cuff causes a moderate to significant increase in the BP reading, and 55% believe that a larger cuff causes a similar decrease in the BP reading. A significant number of practitioners (44%) did not know the Task Force definition of hypertension, including 42% of attendings, 44% of residents, and 50% of nurses. Conclusions. The Task Force and the Working Group recommendations on BP cuff selection need to be reviewed. A new multicenter study, using uniform criteria for cuff selection, may be necessary to establish the accuracy of the published nomogram on normal BP in children. More awareness is required on part of practitioners of the current recommendations on BP measurement and the definition of hypertension. Finally, the labeling of BP cuffs as infant, pediatric, small adult, adult, and large adult is misleading, and such designations should be eliminated. Cuff sizes should be standardized, indicate bladder size, and be uniformly color-coded for convenience.

Treatment of Severe Edema in Children with Nephrotic Syndrome with Diuretics Alone — A Prospective Study

BACKGROUND AND OBJECTIVE Severe edema in children with nephrotic syndrome (NS) may be associated with volume contraction (VC) or volume expansion (VE). Usually, severe edema in children is treated with intravenous (IV) albumin and diuretics, which is appropriate for VC patients. However, in VE patients, this can precipitate fluid overload. The objective of this study was to evaluate treatment of severe edema in NS with diuretics alone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Thirty NS patients with severe edema were enrolled in this prospective study in two phases. VC was diagnosed based on fractional excretion of sodium (FeNa) <1%. VC patients received IV albumin and furosemide. VE patients received IV furosemide and oral spironolactone. On the basis of phase 1 observations, FeNa <0.2% identified VC in 20 phase 2 patients. RESULTS All phase 1 patients had FeNa <1%. Phase 1 patients when reanalyzed based on a FeNa cutoff of 0.2%; it was noted that VC patients had higher BUN, BUN/creatinine ratio, urine osmolality, and lower FeNa and urine sodium compared with VE patients. Similar results were observed in phase 2. VC patients had significantly higher renin, aldosterone, and antidiuretic hormone levels. In phase 2, 11 VE patients received diuretics alone and 9 VC patients received albumin and furosemide. There was no difference in hospital stay and weight loss in VC and VE groups after treatment. CONCLUSIONS FeNa is useful in distinguishing VC versus VE in NS children with severe edema. The use of diuretics alone in VE patients is safe and effective.

Controversies in the management of vesicoureteral reflux: The rationale for the RIVUR study *

UNLABELLED The current management of vesicoureteral reflux (VUR) focuses on the prevention of urinary tract infections (UTI), with curative surgery being limited to those children that fail conservative measures. This is based on the assumption that UTIs are preventable with the use of prophylatic antibiotics, leading to reduction of renal scarring, and the possibility that VUR in children can resolve spontaneously. METHODS Review of the recent literature has demonstrated a growing concern that antibiotic prophylaxis may not lead to prevention of UTIs. Additionally, data indicate that renal scarring may not be preventable with antibiotic prophylaxis or even surgical correction of VUR. An overview of all of the current controversies is presented in this paper. RESULTS Does antibiotic prophylaxis lead to reduction in UTIs in children with VUR? To address this question, the National Institutes of Health have developed a randomized placebo-controlled study of children with VUR (the RIVUR Study), identified following the development of a UTI. CONCLUSIONS There are far reaching consequences of the results of the RIVUR Study. If antibiotic prophylaxis does not prevent UTI in children with VUR, or lead to reduction in renal scarring, does identification of VUR provide any benefits? Perhaps appropriate treatment of UTI may be all that is necessary for preserving renal function. Final answers will have to wait until the completion of this study.

Effectiveness of a Multidisciplinary Clinic in Managing Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Long-term outcome of patients with chronic kidney disease (CKD) correlates with adequacy of predialysis care. This is best provided in a multidisciplinary clinic that integrates the services of a nephrologist with other staff. There is limited data about such clinics in children. The Childrens Hospital of Michigan established a Chronic Renal Insufficiency (CRI) clinic in 2002 to provide comprehensive care to children with CKD. These children receive care from a nephrologist, nurse clinician, transplant coordinator, dietician, social worker, and psychologist. The objective of the study was to compare outcome variables between patients from the CRI clinic and a general nephrology clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective chart review of 44 patients with CKD stages 2 to 4, who were managed in the general nephrology clinic (1996-2001, n = 20) or the CRI clinic (2002-2007, n = 24) for 1 yr before starting renal replacement therapy (RRT). Laboratory parameters, growth, and dialysis access type at time of RRT were compared between the two cohorts. RESULTS At RRT, patients from the CRI clinic had better hemoglobin, lower parathyroid hormone and calcium phosphorus product than patients followed in the general nephrology clinic. More patients from the general nephrology clinic had an unplanned initiation of dialysis compared with patients from the CRI clinic (50% versus 10.5%, P < 0.05). CONCLUSIONS This indicates that children followed in a multidisciplinary clinic have better outcome variables and are more likely to achieve K/DOQI targets at initiation of dialysis. They are better prepared for dialysis with electively planned catheter insertion or functioning arteriovenous grafts/fistulae.