Marco Pennesi

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.

Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.

Prevalence of celiac disease in patients with juvenile chronic arthritis.

We estimated the prevalence of celiac disease in children with juvenile chronic arthritis (JCA), using antiendomysium antibodies as the screening test to select patients for intestinal biopsy. We studied 119 children with JCA and found four patients with antiendomysium antibodies. In three of these patients (2.5%), intestinal biopsy revealed villous atrophy; in the fourth the intestinal mucosa was normal. We conclude that the prevalence of celiac disease is increased in patients with JCA.

Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome

BACKGROUND Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged. METHODS We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing. RESULTS In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations. CONCLUSIONS These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.

Risk factors for poor renal prognosis in children with hemolytic uremic syndrome

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D−STEC− recovered normal renal function compared with 65%–76% of D+STEC+, D+STEC− and D−STEC+ patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D– but STEC+ patients have a significantly better prognosis.

Lupus nephritis in children and adolescents: results of the Italian Collaborative Study

BACKGROUND Lupus nephritis (LN) strongly affects the outcome in children with systemic lupus erythematosus (SLE). Many patients, however, have renal disease at onset, but lack a sufficient number of criteria to be diagnosed as SLE and develop delayed symptoms over time (d-SLE). Data on the clinical course, long-term outcome and predictors of disease progression in children with LN are scant. METHODS The Italian Collaborative Study included 161 paediatric patients with LN who were followed up for a mean of 96 months (range 6-296) in seven paediatric nephrology units. Cox-Mantel regression models were used to identify predictors of disease remission, relapse and progression. RESULTS At 1 year, the proportion of patients in remission was 83.2% (partial) and 53.5% (complete). Renal flares occurred in >50% of patients within 10 years. The intensity of induction treatment correlated significantly with the achievement of remission, while d-SLE, class IV LN and younger age were associated with poor response to treatment and/or with progression to chronic renal failure. CONCLUSIONS The current study provides outcome data on a large paediatric population with LN and underlines the importance of prescribing appropriate induction treatment to all children, regardless of the presence of enough SLE criteria, which may develop several years after the initial diagnosis.

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.

Anti-alpha-gliadin antibodies are not predictive of celiac disease in juvenile chronic arthritis.

Some authors have recently reported an increased level of antigluten antibodies in rheumatoid arthritis, both in the adult and juvenile form. The real meaning of these antibodies is still unclear. We ascertained the levels of antigluten antibodies in a group of children with juvenile chronic arthritis to determine if these antibodies were linked with celiac disease and/or to increased intestinal permeability. In 18 of 53 patients (33.9%), the levels of antigluten antibodies (IgA or IgG) were higher than normal. No correlation was found between the increase in antigluten antibodies and the positive lactulose/ mannitol test, used for determining increased intestinal permeability. In all eight patients undergoing intestinal biopsy due to abnormal levels of antigluten antibodies (IgA class), intestinal mucosa was normal. In conclusion, our study shows that in patients with juvenile chronic arthritis, immunological response to gluten is neither related to celiac disease nor to increased intestinal permeability.

A new mutation in two siblings with cystinosis presenting with Bartter syndrome

Nephropathic cystinosis is a severe autosomal recessive inherited metabolic disease characterized by accumulation of free cystine in lysosomes. Cystinosis can lead to renal failure and multiorgan impairment. Only five cases of cystinosis with associated Bartter syndrome are reported in the literature, and no genetic evaluation has been reported. We describe two siblings with nephropathic cystinosis presenting with features of Bartter syndrome and their genetic pattern.

Effective tacrolimus treatment in a child suffering from severe nephrotic syndrome

Minimal change disease (MCD) therapy includes steroids and, for those forms which are steroid-resistant or strictly steroid-dependent, cyclophosphamide, chlorambucil, cyclosporine [1], or mycophenolate mofetil [2] and levamisole [3] have also been employed as steroidsparing agents. Over the last few years recommendations have appeared in the literature regarding the beneficial role of tacrolimus in cases of adult MCD or focal segmental glomerulosclerosis resistant to cyclosporine and to steroids or which are strictly steroid dependent [4, 5]. We have not found effects similar to those reported in the literature for children and this prompts us to report our experience of a long-term follow-up of a child, aged 17 years, suffering from MCD who was steroid dependent and unresponsive to alkylating agents, cyclosporine and other immunosuppressive drugs, who was treated successfully with tacrolimus. The disease began at the age of 20 months with generalised edema, hypertension (PA 110/77 mmHg), selective proteinuria (10 g/l with 0.1 Cameron index), microscopic hematuria, hypoproteinemia (3.7 g/dl), hypoalbuminemia (0.95 g/dl), hypogammaglobulinemia (0.29 g/dl), hypercholesterolemia (635 mg/dl) and hyperfibrinogenemia (1.1 g/dl). The child was treated initially with prednisone (2 mg/kg/day) with no improvement. Six i.v. infusions of methylprednisolone, every other day, induced complete remission. The strict dependence on high doses of steroids was the characteristic symptom of his disease with a mean of five relapses/year (range four to seven) that always occurred concurrently with any attempted reduction in steroid doses to below 1 mg/kg/day. Given the failure of numerous attempts at immunosuppressive therapy (cyclophosphamide, cyclosporine, levamisole, mycophenolate mofetil) (Table 1) and the devastating side effects of such a prolonged corticosteroid-based therapy (osteopenia, obesity, striae rubrae, moon facies), and on the basis of sporadic reports from the literature [4], a decision was made in July 2000, following a further relapse, to combine tacrolimus at a dose of 0.05 mg/kg/day (divided into two doses) with prednisone. Since then and up to the time of submission of this report the prednisone has been tapered and discontinued while the child has remained in complete remission. Monthly tacrolimus trough blood levels have remained between 8 and 12 ng/ml. There has been a notable improvement in all the above steroid side effects without any notable new adverse effects. The current case report highlights the effectiveness of tacrolimus in a child with MCD who was dependent on