Short-term survival of hyperammonemic neonates treated with dialysis.

BACKGROUND: In severe neonatal hyperammonemia, extracorporeal dialysis (ECD) provides higher ammonium clearance than peritoneal dialysis (PD). However, there are limited outcome data in relation to dialysis modality. METHODS: Data from infants with hyperammonemia secondary to inborn errors of metabolism (IEM) treated with dialysis were collected in six Italian centers and retrospectively analyzed. RESULTS: Forty-five neonates born between 1990 and 2011 were enrolled in the study. Of these, 23 were treated with PD and 22 with ECD (14 with continuous venovenous hemodialysis [CVVHD], 5 with continuous arteriovenous hemodialysis [CAVHD], 3 with hemodialysis [HD]). Patients treated with PD experienced a shorter duration of predialysis coma, while those treated with HD had a shorter ammonium decay time compared with all the other patients (p < 0.05). No difference in ammonium reduction rate was observed between patients treated with PD, CAVHD or CVVHD. Carbamoyl phosphate synthetase deficiency (CPS) was significantly associated with increased risk of death (OR: 9.37 [1.52-57.6], p = 0.016). Predialysis ammonium levels were significantly associated with a composite end-point of death or neurological sequelae (adjusted OR: 1.13 [1.02-1.27] per 100 µmol/l, p = 0.026). No association was found between outcome and dialysis modality. CONCLUSIONS: In this study, a delayed ECD treatment was not superior to PD in improving the short-term outcome of neonates with hyperammonemia secondary to IEM.

Successful early management of a female patient with a metabolic stroke due to ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase deficiency (OTC-D) is a urea cycle disorder caused by dysfunction of ornithine transcarbamylase, which frequently leads to hyperammonemia. Hyperammonemia represents a medical emergency requiring prompt treatment to reduce plasma ammonia levels and prevent severe neurological damage, coma, and death, particularly in patients with acute decompensation-related coma. The clinical symptoms of OTC-D can manifest themselves either at an early stage, which is often associated with severe symptoms, or in later life (late-onset OTC-D), when symptoms may be less severe. There is currently little agreement over diagnostic signs of the condition or the most appropriate therapeutic approach. Hyperammonemia is usually treated with ammonia scavengers, continuous venovenous hemodialysis, and dietary changes. N-carbamylglutamate is approved for the treatment of hyperammonemia in N-acetylglutamate synthetase deficiency and may have efficacy in other urea cycle disorders. METHODS/RESULTS: Here, we report a 13-year-old girl who was diagnosed with OTC-D at the age of 3 years. On this occasion, the patient presented with vomiting, lethargy, and mental confusion. Despite biochemical parameters being within normal ranges, she was comatose within a few hours. She was promptly treated with a combined therapy of continuous venovenous hemodialysis and N-carbamylglutamate, resulting in a gradual normalization of clinical symptoms within 30 hours. No neurological damage was apparent at 18 months after treatment. CONCLUSIONS: This case demonstrates that clinical benefits can be obtained by beginning aggressive treatment of OTC-D within a few hours of the onset of severe neurological symptoms even in the absence of altered biochemical markers.

Encapsulating peritoneal sclerosis in paediatric peritoneal dialysis patients: the experience of the Italian Registry of Pediatric Chronic Dialysis.

BACKGROUND: Paediatric literature about encapsulating peritoneal sclerosis (EPS) is limited and comes primarily from anecdotic experiences. In this study, we described the incidence and characteristics of EPS in a large paediatric chronic peritoneal dialysis (CPD) patient population. METHODS: We reviewed files of patients starting CPD at <16 years of age, recorded from January 1986 to December 2011 by the Italian Registry of Pediatric Chronic Dialysis (n = 712). Moreover, in December 2011, a survey was performed involving all the Italian Pediatric Nephrology Units to report such EPS cases that occurred after CPD withdrawal. RESULTS: Fourteen EPS cases were reported, resulting in a prevalence of 1.9%. The median age of EPS cases was 4.8 years (range 0.6-14.4) at the start of CPD and 14.3 years (6.5-26.8) at EPS diagnosis. Eleven EPS cases received CPD for longer than 5 years. At diagnosis, nine patients were still on CPD, two were on haemodialysis and three were transplanted. In eight patients, the primary renal disease was represented by glomerulopathy, mainly focal segmental glomerulosclerosis (n = 5). In the last 6 months prior to CPD discontinuation, 10 patients were treated with solutions containing more than 2.27% glucose. Peritonitis incidence was 1:26.8 CPD-months, similar to that calculated in children >12 months of age from the same registry (1:28.3 CPD-months). The mortality rate was 43%. A more aggressive course and an association with calcineurin inhibitors were observed in transplanted patients. CONCLUSIONS: Surveillance for EPS should be maintained in high-risk children who received long-term PD even after years from CPD withdrawal.

[Apheresis in children: procedures and outcome]. / Aferesi in eta' pediatrica: procedure e outcome.

Apheresis procedures are used in children to treat an increasing number of conditions by removing different types of substances from the bloodstream. In a previous study we evaluated the first results of our experience in children, emphasizing the solutions adopted to overcome technical difficulties and to adapt adult apheresis procedures to a pediatric population. The aim of the present study is to present data on a larger number of patients in whom apheresis was the main treatment. Ninety-three children (50 m, 43 f) affected by renal and/or extrarenal diseases were included. They were treated with LDL apheresis, protein A immunoadsorption, or plasma exchange. Our therapeutic protocol was the same as described in the previous study. Renal diseases and immunological disorders remained the most common conditions requiring this therapeutic approach. However, hemolytic uremic syndrome (HUS) was no longer the most frequent renal condition to be treated, as apheresis is currently the first treatment option only in cases of atypical HUS. In this series we also treated small children, showing that low weight should no longer be considered a contraindication to apheresis procedures. The low rate of complications and the overall satisfactory clinical results with increasingly advanced technical procedures make a wider use of apheresis in children realistic in the years to come.

TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype.

BACKGROUND AND OBJECTIVES: Mutations in the TRPC6 gene have been recently identified as the cause of late-onset autosomal-dominant focal segmental glomerulosclerosis (FSGS). To extend the screening, we analyzed TRPC6 in 33 Italian children with sporadic early-onset SRNS and three Italian families with adult-onset FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: TRPC6 mutation analysis was performed through PCR and sequencing. The effects of the detected amino acid substitutions were analyzed by bioinformatics tools and functional in vitro studies. The expression levels of TRPC6 and nephrin proteins were evaluated by confocal microscopy. RESULTS: Three heterozygous missense mutations (c.374A>G_p.N125S, c.653A>T_p.H218L, c.2684G>T_p.R895L) were identified. The first new mutation, p.H218L, was found in a 18-year-old boy who presented a severe form of FSGS at the age of 8 years. The second, p.R895L, a new de novo mutation, was identified in a girl with collapsing glomerulosclerosis at the age of 2 years. The former mutation, p.N125S, was found in two siblings with early-onset steroid-resistant nephrotic syndrome (SRNS) at the ages of 4 and 14 years. Renal immunofluorescence revealed upregulated expression of TRPC6 and loss of nephrin in glomeruli. The intracellular calcium concentrations were significantly higher in the cells expressing all mutant TRPC6 channels compared with cells expressing wild-type TRPC6. CONCLUSIONS: Our findings suggest that TRPC6 variants can also be detected in children with early-onset and sporadic SRNS (4 of 33 patients). Moreover, in one patient a new de novo TRPC6 mutation was associated with a rare severe form of childhood collapsing glomerulosclerosis with rapid progression to uremia.

Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations.

BACKGROUND AND OBJECTIVES: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We reviewed the clinical features of 40 patients with NS associated with heterozygous mutations or variants in NPHS1 (n = 7) or NPHS2 (n = 33). Long-term renal survival probabilities were compared with those of a concurrent cohort with idiopathic NS. RESULTS: Patients with a single mutation in NPHS1 received a diagnosis before those with potentially nongenetic NS and had a good response to therapies. Renal function was normal in all cases. For NPHS2, six patients had single heterozygous mutations, six had a p.P20L variant, and 21 had a p.R229Q variant. Age at diagnosis and the response to drugs were comparable in all NS subgroups. Overall, they had similar renal survival probabilities as non-NPHS1/NPHS2 cases (log-rank chi(2) 0.84, P = 0.656) that decreased in presence of resistance to therapy (P < 0.001) and in cases with renal lesions of glomerulosclerosis and IgM deposition (P < 0.001). Cox regression confirmed that the only significant predictor of dialysis was resistance to therapy. CONCLUSIONS: Our data indicate that single mutation or variant in NPHS1 and NPHS2 does not modify the outcome of primary NS. These patients should be treated following consolidated schemes and have good chances for a good long-term outcome.

Effect of carnitine supplementation on lipid profile and anemia in children on chronic dialysis.

We prospectively evaluated the effects of L-carnitine supplementation on plasma free carnitine (FC) levels, serum lipid profile, and erythropoietin (rhEPO) requirement in 24 children treated with peritoneal dialysis (PD; n=16) or hemodialysis (HD; n=8). The study was divided into a 3-month observation period, and a 3-month treatment period during which patients received 20 mg/kg per day of L-carnitine given orally. Clinical, biochemical, and hematological data were collected every 3 months. FC levels were measured in plasma and peritoneal dialysate by tandem mass spectrometry. There were no statistically significant changes in lipid levels, hemoglobin, or rhEPO requirements during the course of the study. Fifteen patients (13 PD, 2 HD) had plasma FC levels measured before and after treatment; FC levels increased from 32.1 +/- 14.1 micromol/l to 80.9 +/- 38.7 micromol/l (P<0.001). In PD patients, dialysate FC losses increased from 106 +/- 78 micromol/day at baseline to 178 +/- 119 micromol/day after supplementation. Positive correlations between FC plasma levels and dialysate levels (R=0.507) or daily excretion (R=0.603) were found after treatment. In our case series, an oral dose of 20 mg/kg per day of L-carnitine restored FC levels and produced a positive carnitine balance with no significant effects on hematological parameters or lipid profile over a 3-month period. Prolonged treatment duration may be required to obtain significant results.

Clinical experience with darbepoietin alfa (NESP) in children undergoing hemodialysis.

Darbepoietin alfa (NESP) is a new long-acting erythropoietin, with a half-life 3 times longer than the old epoietins. In the present study, we evaluated the efficacy of NESP in a group of children on hemodialysis. Seven children, five male and two female, with a mean age of 11.5 +/- 3 years and a mean weight of 34.1 +/- 11 kg, were enrolled in the study. All had been treated for at least 6 months with epoietin alfa at a mean dose of 106 +/- 76 IU/kg 3 times/week i.v. They were then given NESP at a mean dose of 1.59 +/- 1.19 microg/kg once a week i.v., according to the suggested conversion index (weekly epoietin alfa dose/200=weekly NESP dose). Anemia was evaluated at the end of a dialysis session. This was especially important for children less compliant with water restriction. Serum ferritin and percentage transferrin saturation (TSAT) were also monitored, as were dialysis efficacy (Kt/V), blood pressure, and heparin requirements. Before starting the new treatment, all patients had an adequate mean hemoglobin (Hb) level (11.19 +/- 1.7 g/dl) and an adequate iron status (TSAT 24.2 +/- 11.5, serum ferritin 220 +/- 105 mg/dl). Five of the seven patients were also treated with intravenous ferric gluconate (10-20 mg/kg per week). Six children were on antihypertensive treatment. After the 1st month of treatment, we observed an excessive increase in Hb, 12.3 +/- 1.7 g/dl, (P<0.05), with severe hypertension in the youngest two patients (Hb>13 g/dl). A short discontinuation of the medication, followed by restarting at a decreased dosage, allowed us to continue with the treatment. At the 2nd month of follow-up, a mean plasma Hb level of 12.2 +/- 1.2 g/dl was observed, with a NESP mean dose of 0.79 +/- 0.4 microg/kg per week. Steady state was reached at 3 months, with a mean Hb of 11.8 +/- 1.4 g/dl and a mean NESP dose of 0.51 +/- 0.18 microg/kg per week (P<0.05). These results persisted at 6 months of follow-up; only one child had a persistent increase in platelet level (373,000 vs. 555,000). Dialysis efficiency and heparin requirements during dialysis did not change significantly. The high efficacy of NESP allowed a consistent reduction in dosage. The suggested conversion index does not appear to be correct for pediatric patients. Our experience suggests that in this population the correct dose could be 0.25-0.75 microg/kg per week. Hypertension was the only major side effect reported. The influence of NESP on platelet proliferation needs to be further investigated. The single weekly administration of NESP could be effective and beneficial for both patients and clinicians.

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.

Shiga toxin-producing Escherichia coli infections associated with hemolytic uremic syndrome, Italy, 1988-2000.

The mean annual incidence of hemolytic uremic syndrome in persons

Role of non-polio enterovirus infection in pediatric hemolytic uremic syndrome.

Verocytotoxin-producing Escherichia coli(VTEC) infections cause most cases of hemolytic uremic syndrome (HUS); 10-30% of patients, however, are negative for VTEC infection. The etiology of HUS in VTEC-negative cases remains poorly understood. Before the association between VTEC infection and HUS was recognized, sporadic cases of HUS with enterovirus infection were reported in the literature. Since May 1988, most cases of HUS in Italy have been reported to the Italian surveillance system, and in 73% of these, evidence of VTEC infection was demonstrated. The aim of this study was to determine whether the frequency of enteroviral infections was different in the acute phase of VTEC-positive and VTEC-negative HUS. Eighty-nine patients were investigated for enteroviral infection, of whom 58 were VTEC positive and 31 VTEC negative. Two serum samples from each patient were examined for seroconversion to enterovirus (coxsackie, echovirus, and picornavirus) by a complement fixation test. Serological evidence of acute infection with non-polio enterovirus was found in 33 patients (37%) [20/58 (34.5%) VTEC positive and 13/31 (41.9%) VTEC negative]. There was no statistically significant difference between the two groups. These results demonstrate that there are no significant differences for enteroviral infection in VTEC-positive and VTEC-negative patients and, therefore, enteroviral infections should not be considered a cause of HUS in VTEC-negative children.