François Bouissou

Differential Impact of Complement Mutations on Clinical Characteristics in Atypical Hemolytic Uremic Syndrome

Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.

Renal Phenotypes Related to Hepatocyte Nuclear Factor-1β (TCF2) Mutations in a Pediatric Cohort

The hepatocyte nuclear factor-1beta encoded by the TCF2 gene plays a role for the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for the maturity-onset diabetes of the young type 5 associated with renal manifestations. Several observations have suggested that TCF2 mutations may be involved in restricted renal phenotypes. Eighty children (median age at diagnosis 0.2 yr) with renal cysts, hyperechogenicity, hypoplasia, or single kidneys were studied. Quantitative multiplex PCR amplification of short fluorescence fragments for the search of large genomic rearrangements and sequencing for the detection of point mutations were performed. TCF2 anomalies were detected in one third of patients (25 of 80). The main alteration was the complete deletion of the TCF2 gene detected in 16 patients. Family screening revealed de novo TCF2 anomalies in nine of 17 probands with a high prevalence of deletions (seven of nine). TCF2 anomalies were associated with bilateral renal anomalies (P < 0.001) and bilateral cortical cysts (P < 0.001). However, abnormal renal function, detected in 40% of patients, was independent of the TCF2 genotype. No difference in renal function or severity of renal morphologic lesions was observed between patients with a TCF2 deletion and those with point mutations. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. These findings have important implications in the diagnosis of patients with renal dysplasia with cysts and their follow-up.

Genetic Investigation of Autosomal Recessive Distal Renal Tubular Acidosis: Evidence for Early Sensorineural Hearing Loss Associated with Mutations in the ATP6V0A4 Gene

Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.

Deletion of the mitochondrial DNA in a case of de Toni-Debre-Fanconi syndrome and Pearson syndrome.

We report a patient with Pearson syndrome with failure to thrive, exocrine pancreas insufficiency, growth hormone deficiency and severe tubular dysfunction. The patient had no signs of liver involvement. Normal respiratory chain enzyme activity was found in the lymphocytes, but a mitochondrial DNA deletion was demonstrated in lymphocytes and in the kidney. Polymerase chain reaction amplification and sequence analysis revealed the presence of the 4,977 base pair “common” deletion in the mitochondrial genome. Our findings support the view that tubulopathies of unknown origin may be related to mitochondrial respiratory chain deficiency.

Association of Procalcitonin With Acute Pyelonephritis and Renal Scars in Pediatric UTI

BACKGROUND AND OBJECTIVE: Urinary tract infections (UTIs) are common childhood bacterial infections that may involve renal parenchymal infection (acute pyelonephritis [APN]) followed by late scarring. Prompt, high-quality diagnosis of APN and later identification of children with scarring are important for preventing future complications. Examination via dimercaptosuccinic acid scanning is the current clinical gold standard but is not routinely performed. A more accessible assay could therefore prove useful. Our goal was to study procalcitonin as a predictor for both APN and scarring in children with UTI. METHODS: A systematic review and meta-analysis of individual patient data were performed; all data were gathered from children with UTIs who had undergone both procalcitonin measurement and dimercaptosuccinic acid scanning. RESULTS: A total of 1011 patients (APN in 60.6%, late scarring in 25.7%) were included from 18 studies. Procalcitonin as a continuous, class, and binary variable was associated with APN and scarring (P < .001) and demonstrated a significantly higher (P < .05) area under the receiver operating characteristic curve than either C-reactive protein or white blood cell count for both pathologies. Procalcitonin ≥0.5 ng/mL yielded an adjusted odds ratio of 7.9 (95% confidence interval [CI]: 5.8–10.9) with 71% sensitivity (95% CI: 67–74) and 72% specificity (95% CI: 67–76) for APN. Procalcitonin ≥0.5 ng/mL was significantly associated with late scarring (adjusted odds ratio: 3.4 [95% CI: 2.1–5.7]) with 79% sensitivity (95% CI: 71–85) and 50% specificity (95% CI: 45–54). CONCLUSIONS: Procalcitonin was a more robust predictor compared with C-reactive protein or white blood cell count for selectively identifying children who had APN during the early stages of UTI, as well as those with late scarring.

Procalcitonin is a Predictor for High-Grade Vesicoureteral Reflux in Children: Meta-Analysis of Individual Patient Data

OBJECTIVE To assess the predictive value of procalcitonin, a serum inflammatory marker, in the identification of children with first urinary tract infection (UTI) who might have high-grade (≥3) vesicoureteral reflux (VUR). STUDY DESIGN We conducted a meta-analysis of individual data, including all series of children aged 1 month to 4 years with a first UTI, a procalcitonin (PCT) level measurement, cystograms, and an early dimercaptosuccinic acid scan. RESULTS Of the 152 relevant identified articles, 12 studies representing 526 patients (10% with VUR ≥3) were included. PCT level was associated with VUR ≥3 as a continuous (P = .001), and as a binary variable, with a 0.5 ng/mL preferred threshold (adjusted OR, 2.5; 95% CI, 1.1 to 5.4). The sensitivity of PCT ≥0.5 ng/mL was 83% (95% CI, 71 to 91) with 43% specificity rate (95% CI, 38 to 47). In the subgroup of children with a positive results on dimercaptosuccinic acid scan, PCT ≥0.5 ng/mL was also associated with high-grade VUR (adjusted OR, 4.8; 95% CI, 1.3 to 17.6). CONCLUSIONS We confirmed that PCT is a sensitive and validated predictor strongly associated with VUR ≥3, regardless of the presence of early renal parenchymal involvement in children with a first UTI.

Prospective, Randomized Trial Comparing Short and Long Intravenous Antibiotic Treatment of Acute Pyelonephritis in Children: Dimercaptosuccinic Acid Scintigraphic Evaluation at 9 Months

OBJECTIVE. We report a prospective, randomized, multicenter trial that compared the effect of 3 vs 8 days of intravenous ceftriaxone treatment on the incidence of renal scarring at 6 to 9 months of follow-up in 383 children with a first episode of acute pyelonephritis. METHODS. After initial treatment with intravenous netilmicin and ceftriaxone, patients were randomly assigned to either 5 days of oral antibiotics (short intravenous treatment) or 5 days of intravenous ceftriaxone (long intravenous treatment). Inclusion criteria were age 3 months to 16 years and first acute pyelonephritis episode, defined by fever of >38.5°C, C-reactive protein level of >20 mg/L, and bacteriuria at >105/mL. All patients underwent 99m technetium-dimercaptosuccinic acid scintigraphy 6 to 9 months after inclusion. A total of 548 children were included, 48 of whom were secondarily excluded and 117 of whom were lost to follow-up or had incomplete data; therefore, 383 children were eligible, 205 of them in the short intravenous treatment group and 178 in the long intravenous treatment group. RESULTS. At inclusion, median age was 15 months, median duration of fever was 43 hours, and median C-reactive protein level was 122 mg/L. A total of 37% (143 of 383) of patients had a vesicoureteral reflux grades 1 to 3. Patient characteristics at inclusion were similar in both groups, except for a significantly higher proportion of girls in the short intravenous treatment group. The frequency of renal scars at scintigraphy was similar in both groups. Multivariate analysis demonstrated that renal scars were significantly associated with increased renal height at initial ultrasound and with the presence of grade 3 vesicoureteric reflux. CONCLUSIONS. The incidence of renal scars was similar in patients who received 3 days compared 8 days of intravenous ceftriaxone. Increased renal height at initial ultrasound examination and grade 3 vesicoureteric reflux were significant risk factors for renal scars.

Risk factors for chronic rejection in pediatric renal allograft recipients

Abstract. To determine the risk factors predictive of graft loss from chronic rejection in pediatric renal allograft recipients, we reviewed the collaborative study database of the Société de Néphrologie Pédiatrique which registered 314 grafts from January 1987 to December 1991. Of the 289 grafts analyzed, 71 failed during follow-up, chronic rejection being the most common cause of graft loss (35%). The clinical features of the chronic rejection group (n = 25) were compared with those of the group without failure (n = 218). The variables tested by monovariate analysis were cyclosporine dose at 1 year, donor type, donor and recipient age, and acute rejection episodes. The incidence of graft loss due to chronic rejection was 4% (4/109) in patients who had no acute rejection and 16% (21/134) in those with at least one acute rejection episode (P = 0.002). Donor age (≤5 years) was a risk factor for chronic rejection (P = 0.024). Recipient age and donor type were not significantly different between the chronic rejection group and the control group. Using time-dependent covariates, the risk factors were an acute rejection episode (P = 0.003) and low cyclosporine doses at 1 year (P = 0.02). We conclude that acute rejection and low cyclosporine doses in these pediatric patients were risk factors for graft loss due to chronic rejection.

Long-term effects of cyclophosphamide therapy in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome

BACKGROUND It has been demonstrated that alkylating agents such as cyclophosphamide (CYP) are effective in reducing the risk of relapse in frequently relapsing (FRNS) and steroid-dependent nephrotic syndrome (SDNS). Little is known about prognostic factors in SDNS and FRNS treated by CYP. The objectives of this study are to determine long-term outcomes and factors associated with sustained remission in these patients. METHODS We retrospectively studied the data from 143 children (104 boys) with SDNS and FRNS treated with CYP in six centres over 15 years. Relapse-free survival was estimated by Kaplan-Meier method. The determinants of long-term remission were assessed by univariate and multivariate analyses using Cox proportional hazard models. RESULTS Median age at diagnosis was 3.7 years (interquartile range: IQR 2.3-5.9), and median follow-up was 7.8 years (IQR 4.0-11.8). CYP treatment was introduced after a median time of 1.7 years (IQR 0.7-5.9) after diagnosis. Patients received a median cumulative dose of 168 mg/kg (IQR 157-197) body weight. Relapse-free survival was 65%, 44%, 27% and 13% after 6 months, 1 year, 2 years and 5 years, respectively. In multivariate analysis, sustained remission >2 years was associated with age at treatment >5 years (P = 0.02) and cumulative dose of CYP >170 mg/kg (P = 0.02). Frequently relapsing versus steroid-dependent status and female gender were predictors of borderline significance. Height and body mass index standard deviation score were significantly influenced by CYP treatment. CONCLUSION In our study, long-term efficacy of cyclophosphamide in steroid-responsive nephrotic syndrome is disappointing. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents.

Pharmacokinetics of prednisolone in children with the nephrotic syndrome

The aim of this study was to establish whether the criteria for the clinical effectiveness of steroids are correlated with the pharmacokinetics of prednisolone in children treated with prednisone during an attack of idiopathic nephrotic syndrome (INS). Thirteen patients with nephrosis were included. Prednisolone, prednisone and cortisol levels were measured using a specific high-performance liquid chromatography assay after an oral dose of 1 mg/kg body weight of prednisone taken at the onset of the disease. All the pharmacokinetic parameters, including the conversion of prednisone to prednisolone were similar to the data already published in children with INS. No correlation was found between the values of pharmacokinetic parameters and criteria of clinical effectiveness. Hypo-albuminaemia was significantly correlated with the area under the plasma-concentration curve but not with the elimination half-life of prednisolone. Moreover, the prednisolone elimination half-life correlated with the urinary exretion of 17-hydroxycorticosteroids achieved in the first 6h. The present study suggests that routine measurements of prednisolone kinetics do not help when assessing the treatment of children with INS.