Graziella Zacchello

Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial.

OBJECTIVES. Febrile urinary tract infections are common in children and associated with the risk for renal scarring and long-term complications. Antimicrobial prophylaxis has been used to reduce the risk for recurrence. We performed a study to determine whether no prophylaxis is similar to antimicrobial prophylaxis for 12 months in reducing the recurrence of febrile urinary tract infections in children after a first febrile urinary tract infection. METHODS. The study was a controlled, randomized, open-label, 2-armed, noninferiority trial comparing no prophylaxis with prophylaxis (co-trimoxazole 15 mg/kg per day or co-amoxiclav 15 mg/kg per day) for 12 months. A total of 338 children who were aged 2 months to <7 years and had a first episode of febrile urinary tract infection were enrolled: 309 with a confirmed pyelonephritis on a technetium 99m dimercaptosuccinic acid scan with or without reflux and 27 with a clinical pyelonephritis and reflux. The primary end point was recurrence rate of febrile urinary tract infections during 12 months. Secondary end point was the rate of renal scarring produced by recurrent urinary tract infections on technetium 99m dimercaptosuccinic acid scan after 12 months. RESULTS. Intention-to-treat analysis showed no significant differences in the primary outcome between no prophylaxis and prophylaxis: 12 (9.45%) of 127 vs 15 (7.11%) of 211. In the subgroup of children with reflux, the recurrence of febrile urinary tract infections was 9 (19.6%) of 46 on no prophylaxis and 10 (12.1%) of 82 on prophylaxis. No significant difference was found in the secondary outcome: 2 (1.9%) of 108 on no prophylaxis versus 2 (1.1%) of 187 on prophylaxis. Bivariate analysis and Cox proportional hazard model showed that grade III reflux was a risk factor for recurrent febrile urinary tract infections. Whereas increasing age was protective, use of no prophylaxis was not a risk factor. CONCLUSIONS. For children with or without primary nonsevere reflux, prophylaxis does not reduce the rate of recurrent febrile urinary tract infections after the first episode.

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

Abstract This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac (n=103) or CyA microemulsion (n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baselinecharacteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute re-jection (36.9%) compared with CyA therapy (59.1%) (P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group (P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62±20 ml/min per 1.73 m2, n=84) than in the CyA group (56±21 ml/min per 1.73 m2, n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences (P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.

Extracorporeal photochemotherapy for paediatric patients with graft‐versus‐host disease after haematopoietic stem cell transplantation

Summary. This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft‐versus‐host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8·6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5‐year overall survival was 69% for responding patients vs 12% for non‐responders (P = 0·001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5‐year overall survival was 96% for responders vs 58% for non‐responders (P = 0·04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition.

Coenzyme Q10 (CoQ10) deficiency has been associated with various clinical phenotypes, including an infantile multisystem disorder. The authors report a 33-month-old boy who presented with corticosteroid-resistant nephrotic syndrome in whom progressive encephalomyopathy later developed. CoQ10 was decreased both in muscle and in fibroblasts. Oral CoQ10 improved the neurologic picture but not the renal dysfunction.

Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial

Objective To compare the efficacy of oral antibiotic treatment alone with treatment started parenterally and completed orally in children with a first episode of acute pyelonephritis. Design Multicentre, randomised controlled, open labelled, parallel group, non-inferiority trial. Setting 28 paediatric units in north east Italy. Participants 502 children aged 1 month to <7 years with clinical pyelonephritis. Intervention Oral co-amoxiclav (50 mg/kg/day in three doses for 10 days) or parenteral ceftriaxone (50 mg/kg/day in a single parenteral dose) for three days, followed by oral co-amoxiclav (50 mg/kg/day in three divided doses for seven days). Main outcomes measures Primary outcome was the rate of renal scarring. Secondary measures of efficacy were time to defervescence (<37�C), reduction in inflammatory indices, and percentage with sterile urine after 72 hours. An exploratory subgroup analysis was conducted in the children in whom pyelonephritis was confirmed by dimercaptosuccinic acid (DMSA) scintigraphy within 10 days after study entry. Results Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), difference in risk −4%, 95% confidence interval −11.1% to 3.1%) and secondary outcomes (time to defervescence 36.9 hours (SD 19.7) v 34.3 hours (SD 20), mean difference 2.6 (−0.9 to 6.0); white cell count 9.8�109/l (SD 3.5) v 9.5�109/l (SD 3.1), mean difference 0.3 (−0.3 to 0.9); percentage with sterile urine 185/186 v 203/204, risk difference −0.05% (−1.5% to 1.4%)). Similar results were found in the subgroup of 278 children with confirmed acute pyelonephritis on scintigraphy at study entry. Conclusions Treatment with oral antibiotics is as effective as parenteral then oral treatment in the management of the first episode of clinical pyelonephritis in children. Trial registration Clinical Trials NCT00161330.

Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease

Photopheresis (ECP) is a new type of photochemotherapy, used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8‐methoxypsoralen (8‐MOP) and ultraviolet light A (UVA) in an extracorporeal system and then reinfused. Skin exposure to 8‐MOP and UVA (PUVA) has been shown to relieve cutaneous symptoms of graft‐versus‐host disease (GVHD) in bone marrow transplant (BMT) recipients. ECP, which is similar in some ways to PUVA, has been used in this study to treat four paediatric patients who developed chronic GVHD following BMT and in whom GVHD had failed to respond to conventional immunosuppressive therapy. Following ECP, skin lesions cleared almost completely and pulmonary function tests improved in two of three patients with cutaneous and lung involvement. Serum bilirubin and transaminases gradually normalized, and γGT decreased considerably in the remaining patient who had a severe cholestatic hepatopathy. The Karnofsky performance score increased to 90% in the three patients with positive responses to ECP and remained unchanged (40%) in the patient who did not respond. Immunosuppressive therapy was reduced in three patients and eventually discontinued in two. No significant side‐effects were observed during the treatment. Our results suggest that ECP is a non‐aggressive treatment that may benefit patients with chronic GVHD who do not respond to standard immunosuppressive therapy.

Is Serum Cystatin C a Sensitive Marker of Glomerular Filtration Rate (GFR)? A Preliminary Study on Renal Transplant Patients

Human cystatin C is a basic low molecular mass protein (13,359 Dalton) freely filtered through the glomerulus and almost completely re-absorbed and catabolized by proximal tubular cells. We measured serum cystatin C in 38 kidney transplant patients (23 males, 15 females) aged between 6 and 32 years. To assess renal function, serum and urinary creatinine were also determined in all patients, and creatinine clearance was finally calculated. Cystatin C was determined by a particle-enhanced turbidimetric assay, and creatinine was measured by gas chromatography-mass spectrometry. To compare the diagnostic efficiency of cystatin C with that of creatinine, inulin clearance was performed on 12 renal transplant patients, and receiver operating characteristic (ROC) analysis was applied. The results of this study demonstrate that serum cystatin C significantly increases in renal transplant patients with reduced creatinine clearance (< 70 mL/min per 1.73 m2) and that the diagnostic accuracy of serum cystatin C is better than of serum creatinine. Cystatin C may be utilized as a very marker of reduced GFR.

Evaluation of glomerular and nonglomerular hematuria by phase-contrast microscopy*

Glomerular and nonglomerular origins of hematuria may be identified by assessment of the shape and size of the excreted red blood cells. We examined 380 urine specimens from 179 children with hematuria (greater than or equal to 3500 RBC/minute) with phase-contrast microscopy. In 106 cases, the cause was known; the results agreed with the clinical, histologic, and laboratory diagnosis in 63 of 65 subjects (97%) with glomerulopathies and in 39 of 41 (95%) with nonglomerular hematuria. Casts were found in 54% of the specimens from the children with definite glomerular hematuria. Phase-contrast microscopic examination of red blood cells in the urine is a simple, inexpensive, and noninvasive technique that permits an accurate distinction between glomerular and nonglomerular bleeding in pediatric patients.

Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodialysis

Ten children with renal failure (age range 2 years 6 months to 18 years 9 months; median 11 years 10 months), maintained by long-term hemodialysis, had successful correction of their anemia after intravenous administration of recombinant human erythropoietin in a dosage escalating every 2 weeks (75 to 150 to 300 to 450 IU/kg/wk). Mean hemoglobin concentration increased from 6.4 +/- 0.9 to 11.5 +/- 1.0 gm/dl. Blood cell counts used to evaluate the correction of anemia were done after dialysis; this was especially important for children less compliant with water restriction. The higher hemoglobin concentration resulted in improvement of the quality of life, a greater tolerance for physical effort (exercise tolerance doubled and the ventilatory anaerobic threshold increased significantly), correction of some subclinical central nervous system abnormalities detected by evoked potentials testing, and reduction of bleeding time. Few side effects were noted; severe hypertension developed in one patient when postdialysis hematocrit was only 28%, and there were two episodes of hypertransaminasemia with no other evidence of liver dysfunction. We conclude that in children with renal failure the use of recombinant human erythropoietin to correct anemia is safe and strongly advisable, because of the resolution of many of the symptoms correlated with anemia.

Methylxanthines Increase Renal Calcium Excretion in Preterm Infants

To determine the effect of a short course of methylxanthines on renal function and on urinary calcium excretion, 20 premature neonates affected by apnea or moderate respiratory distress syndrome were randomly assigned to either a theophylline treatment or to a caffeine treatment group. The protocol included a 24-hour pretreatment study period (I) and a subsequent 24-hour period (II) following 5 days of theophylline (loading dose 5 mg/kg i.v., maintenance dose 2.5 mg/kg/12 h) or caffeine (loading dose 10 mg/kg i.v., maintenance dose 2.5 mg/kg/12 h) administration. Pre- and postxanthine treatment serum sodium, potassium, calcium and phosphorus remained stable, while serum creatinine decreased significantly (p < 0.05). Furthermore, from period I to period II, sodium urine excretion, fractional Na excretion and creatinine clearance remained statistically comparable in both study groups, along with a significant increase (p < 0.05) in calciuria, urinary Ca/creatinine and urinary Ca/Na. Predose caffeine and theophylline serum levels, assessed on the 5th day of treatment, were 12.8 +/- 1.8 and 7.9 +/- 1.7 micrograms/ml, respectively. Compared to control healthy untreated prematures, the studied premature infants showed a statistically significant increase in urine calcium excretion (10- to 15-fold), which was more evident in the theophylline group. Our data suggest further investigation to determine the long-term renal effects of methylxanthines in premature neonates, to improve assessment of the risk of nephrocalcinosis and osteopenia, in particular in association with various diuretic therapies.