Angela La Manna

Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up

We report the recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection, aged 2 months to 3 years. They were prepared by a working group of the Italian Society of Pediatric Nephrology after careful review of the available literature and a consensus decision, when clear evidence was not available.

ROBO2 Gene Variants Are Associated with Familial Vesicoureteral Reflux

The SLIT2 receptor ROBO2 plays a key role in the formation of the ureteric bud, and its inactivation in mice leads to supernumerary ureteric bud development, lack of ureter remodeling, and improper insertion of the ureters into the bladder. Recently, two heterozygous ROBO2 missense mutations were identified in two families with primary vesicoureteral reflux occurring in combination with congenital anomalies of the kidney and urinary tract (VUR/CAKUT). This study investigated a possible causal role of ROBO2 gene variants in 95 unrelated patients with primary VUR (n = 78) or VUR/CAKUT. Eighty-two percent of all patients had a family history of genitourinary anomalies. Twenty-four ROBO2 gene variants were identified by direct sequencing of all 26 exons and the exon-intron boundaries. Of these, four led to amino acid substitutions: Gly328Ser, Asn515Ile, Asp766Gly, and Arg797Gln. When the families were examined, the missense variants co-segregated with VUR (three families) or VUR/CAKUT (one family). These variants were not found in 190 control subjects, and the affected amino acids have been conserved through evolution. In conclusion, a relatively high frequency of ROBO2 variants (5.1%) was found in familial cases; however, functional studies and validation in other cohorts are warranted.

HIGH INCIDENCE OF A GENERALLY SMALL KIDNEY AND PRIMARY VESICOURETERAL REFLUX

PURPOSE We distinguished the scintigraphy pattern of congenital reflux nephropathy from that of acquired scarring in children with primary vesicoureteral reflux. MATERIALS AND METHODS We retrospectively evaluated the frequency and pattern of renal scintigraphy abnormalities in 41 patients with prenatally detected primary vesicoureteral reflux and in 322 with a mean age plus or minus standard deviation of 3.6 + or - 1 years in whom primary reflux was detected after urinary tract infection. Dimercapto-succinic acid scintigraphy was performed 4 to 6 and 1 to 4 months after reflux was diagnosed and/or the infection was cured in patients with urinary tract infection and prenatal detection, respectively. RESULTS We identified 3 patterns of renal damage, including overall decreased uptake of renal radionuclide that was 20% to 40% of relative uptake, focal defects in uptake and shrunken kidney with relative uptake less than 20%. Scintigraphy revealed renal damage in 12 prenatally detected cases of vesicoureteral reflux, including overall decreased uptake in 58% and shrunken kidney in 42%, and in 111 cases of reflux detected at urinary tract infection, including overall decreased uptake in 50%, uptake focal defects in 37% and shrunken kidney in 13%. In the urinary tract infection group overall decreased uptake was present in 25 of 90 boys and in 40 of 232 girls (p = 0.05). Of these children 15% of the girls had uptake focal defects and 17% had overall decreased uptake. Overall decreased uptake and uptake focal defects were significantly more common in kidney-ureter units with reflux grade 4 or greater than in those with grade 3 or less (p = 0. 00001 and 0.027, respectively). CONCLUSIONS When assuming that overall decreased radionuclide uptake indicates congenital reflux nephropathy and uptake focal defects indicate postnatal acquired scarring, congenital reflux nephropathy appears to be an important cause of renal damage in children with primary vesicoureteral reflux even beyond the neonatal age and even in girls. This finding is of interest because postnatally acquired scarring may but congenital reflux nephropathy may not be prevented.

Permanent renal parenchymal defects after febrile UTI are closely associated with vesicoureteric reflux

The finding of scintigraphic renal defects in children with febrile urinary tract infection (UTI) even in the absence of vesicoureteric reflux (VUR) has led to the conclusion that VUR is a weak predictor of renal defects in these patients. We used isotopic cystography (IC) for diagnosis of VUR in children with febrile UTI. Dimercaptosuccinic acid renal scintigraphy was performed 6 months after cure of the last UTI. Renal defects were defined by the finding of focal defects of radionuclide uptake and/or by a split renal function <43%. The study included 206 children with primary VUR and 77 without VUR. Among the subjects with and without VUR, respectively, renal defects were found in 40 and 6% (p=0.0001), focal uptake defects in 33 and 5% (p=0.0001) and split renal function <43% in 26 and 5% (p=0.0001). Permanent renal defects in children with febrile UTI are closely associated with VUR. The possibility that a child will have permanent renal defects can reasonably be ruled out on the basis of the absence of VUR by IC.

A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity.

Vesicoureteral reflux (VUR) is the most common disease of the urinary tract in children. In order to identify gene(s) involved in this complex disorder, we performed a genome-wide search in a selected sample of 31 patients with primary VUR from eight families originating from southern Italy. Sixteen additional families with 41 patients were included in a second stage. Nonparametric, affected-only linkage analysis identified four genomic areas on chromosomes 1, 3, and 4 (p < 0.05); the best result corresponded to the D3S3681-D3S1569 interval on chromosome 3 (nonparametric linkage score, NPL = 2.75, p = 0.008). This region was then saturated with 26 additional markers, tested in the complete group of 72 patients from 24 families (NPL = 2.01, p = 0.01). We identified a genomic area on 3q22.2–23, where 26 patients from six multiplex families shared overlapping haplotypes. However, we did not find evidence for a common ancestral haplotype. The region on chromosome 1 was delimited to 1p36.2–34.3 (D1S228-D1S255, max. NPL = 1.70, p = 0.03), after additional fine typing. Furthermore, on chromosome 22q11.22–12.3, patients from a single family showed excess allele sharing (NPL = 3.35, p = 0.015). Only the chromosome 3q region has been previously reported in the single genome-wide screening available for primary VUR. Our results suggest the presence of several novel loci for primary VUR, giving further evidence for the genetic heterogeneity of this disorder.

Puberty is associated with increased deterioration of renal function in patients with CKD: data from the ItalKid Project

Objective To analyse the timing of end stage renal disease in children with chronic kidney disease (CKD). Design A population-based cohort study. Setting A nationwide registry (ItalKid Project) collecting information on all patients with CKD aged <20 years. Patients 935 children with CKD secondary to renal hypodysplasia with or without urologic malformation. In a subgroup of patients (n=40) detailed pubertal staging was analysed in relation to CKD progression. Main outcome measures Kidney survival (KS) was estimated using renal replacement therapy (RRT) as the end-point. Puberty was staged by identifying the pubertal growth spurt. Results A non-linear decline in the probability of KS was observed, with a steep decrease during puberty: the probability of RRT was estimated to be 9.4% and 51.8% during the first and second decades of life, respectively. A break-point in the KS curve was identified at 11.6 and 10.9 years of age in male and female patients, respectively. Conclusions The present analysis suggests that puberty is associated with increased deterioration of renal function in CKD. The mechanism(s) underlying this unique and specific (to children) pattern of progression have not yet been identified, but it may be that sex hormones play a role in this puberty-related progression of CKD.

Recurrent Abdominal Pain in Childhood Urolithiasis

OBJECTIVE: Our goal was to establish the clinical presentation and features of pain attacks in children with recurrent abdominal pain (RAP) and urolithiasis. METHODS: We compared the rate of previous appendectomy among 100 consecutive patients with that of 270 control subjects. We also compared the frequency of pain attacks with that reported by children with functional or organic gastrointestinal RAP. RESULTS: Fifty-three patients had no history of dysuria or gross hematuria, and only 35 had hematuria at the first visit; 41 patients were evaluated for urolithiasis only because of a family history of kidney stones associated with RAP. Twenty-nine patients had been previously hospitalized for abdominal symptoms. Sixteen patients and 4 control subjects (1.5%) had undergone a previous appendectomy (P < .0001). Two to 28 months before the diagnosis of urolithiasis, 37 patients underwent abdominal ultrasonography, which did not show urinary stones. Sixty-nine percent of subjects younger than 8 years of age had central/diffuse abdominal pain. The mean frequency of pain attacks was 4 to 9 times lower than in patients with functional or organic gastrointestinal RAP. CONCLUSIONS: Because of the inconstant occurrence of dysuria and hematuria, the location of pain in areas other than the flank, and the lack of calculi shown on imaging studies performed after pain attacks, the urologic origin of pain may be overlooked and ineffective procedures performed. The possibility of urolithiasis should be considered in children with RAP who have a family history of urolithiasis and/or infrequent pain attacks, even when dysuria and hematuria are lacking, and in younger children even when pain is not lateral.

Chronic interstitial cystitis and systemic lupus erythematosus in an 8-year-old girl

Abstract. An 8-year-old girl with systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis had chronic interstitial cystitis (CIC) early in the course of SLE. The early occurrence of CIC, the lack of intestinal symptoms, the association with vesicoureteric reflux, and the improvement of CIC during therapy with cyclosporin A were the prominent features of the patient reported here.

Renal Calyceal Microlithiasis: Clinical Presentation May Precede Sonographic Evidence

Calyceal microlithiasis (CM) is characterized by the sonographic finding of hyperechogenic spots less than 3 mm in diameter in renal calyces, and it may be the first step in calculus formation. From January 1992 to January 1998, we have observed 216 children with CM. The present report deals with 34 of them in whom renal sonography was negative at first observation and the diagnosis of CM was made only on repeated sonographic examinations. The presenting symptoms were recurrent abdominal pain, dysuria, and hematuria occuring alone or in combination. Half of the patients had hypercalciuria. A history of urolithiasis in at least one first- or second-degree relative was present in 85% of patients. Renal sonography was repeated after 6-22 months (mean 11) and showed unilateral CM in 16 subjects and bilateral in18. The finding of CM may be preceded by a period of time when symptoms and/or signs are present while microcalculi are not yet detectable. Repeated ultrasound examinations may be needed not only in patients with hypercalciuria but also in those with recurrent abdominal pain, dysuria, and/or hematuria not associated with hypercalciuria. Clin Pediatr. 1999;38:521-524

Catch-up growth in children with vesico-ureteric reflux

Abstract. A longitudinal retrospective study of height Z score (HZ score) and weight-for-height index (WHI) was performed on 94 pre-pubertal children with vesico-ureteric reflux (VUR) and normal creatinine clearance followed for 1 – 6.8 years (mean 3.1 years). Thirty patients had bilateral VUR with scintigraphic signs of renal scarring (B+), 17 had bilateral VUR without renal scarring (B – ), 27 had unilateral VUR with (U+) and 20 unilateral VUR without (U – ) renal scarring. Thirty-three patients received only antimicrobial medication and 61 underwent successful antireflux operation. The increase in HZ score and WHI during the 1st year of follow-up was significantly (P = 0.001 and 0.00003, respectively) higher than during the 2nd year. At first visit, B+ subjects had an average WHI and HZ score that were significantly (P = 0.02 and 0.04, respectively) lower than the other groups of patients together. At last visit this difference was not significant. In B+ subjects, the WHI and HZ score at last visit were significantly (P = 0.04 for both) higher than at the first visit. B+ patients fully recover their body growth deficit compared with other groups of VUR subjects after medical and/or surgical therapy.