Fabio Paglialonga

Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.

Clinical relevance of shiga toxin concentrations in the blood of patients with hemolytic uremic syndrome

Background: Intestinal infections with Shiga toxin-producing Escherichia coli (STEC) in children can lead to the hemolytic uremic syndrome (HUS). Shiga toxins (Stx) released in the gut by bacteria enter the blood stream and target the kidney causing endothelial injury. Free toxins have never been detected in the blood of HUS patients, but they have been found on the surface of polymorphonuclear leukocytes (PMN). Methods: With respect to their clinical features, the clinical relevance of the amounts of serum Stx (cytotoxicity assay with human endothelial cells) and PMN-bound Stx (cytofluorimetric assay) in 46 patients with STEC-associated HUS was evaluated. Results: Stx-positive PMN were found in 60% of patients, whereas negligible amounts of free Stx were detected in the sera. Patients with high amounts of Stx on PMN showed preserved or slightly impaired renal function (incomplete form of HUS), whereas cases with low amounts of Stx usually presented evidence of acute renal failure. Conclusions: These observations suggest that the extent of renal damage in children with STEC-associated HUS could depend on the concentration of Stx present on their PMN and presumably delivered by them to the kidney. As previously shown by experimental models from our laboratory, high amounts of Stx could induce a reduced release of cytokines by the renal endothelium, with a consequent lower degree of inflammation. Conversely, low toxin amounts can trigger the cytokine cascade, provoking inflammation, thereby leading to tissue damage.

Shiga Toxins Present in the Gut and in the Polymorphonuclear Leukocytes Circulating in the Blood of Children with Hemolytic-Uremic Syndrome

ABSTRACT Hemolytic-uremic syndrome, the main cause of acute renal failure in early childhood, is caused primarily by intestinal infections from some Escherichia coli strains that produce Shiga toxins. The toxins released in the gut are targeted to renal endothelium after binding to polymorphonuclear leukocytes. The presence of Shiga toxins in the feces and the circulating neutrophils of 20 children with hemolytic uremic syndrome was evaluated by the Vero cell cytotoxicity assay and flow cytometric analysis, respectively. The latter showed the presence of Shiga toxins on the polymorphonuclear leukocytes of 13 patients, 5 of whom had no other microbiologic or serologic evidence of infection by Shiga toxin-producing Escherichia coli. A positive relationship was observed between the amounts of Shiga toxins released in the intestinal lumen and those released in the bloodstream. The toxins were detectable on the neutrophils for a median period of 5 days after they were no longer detectable in stools. This investigation confirms that the immunodetection of Shiga toxins on neutrophils is a valuable tool for laboratory diagnosis of Shiga toxin-producing Escherichia coli infection in hemolytic-uremic syndrome and provides clues for further studies on the role of neutrophils in the pathogenesis of this syndrome.

Similarity of Shiga Toxin–producing Escherichia coli O104:H4 Strains from Italy and Germany

To the Editor: Since the beginning of May 2011, a large outbreak of infections associated with Shiga toxin (Stx)–producing Escherichia coli (STEC) O104:H4 has occurred in Germany (1). The outbreak showed 3 unusual features: 1) a large proportion of case-patients with hemolytic uremic syndrome (HUS); 2) HUS in adults, although it usually affects children; and 3) frequent development of neurologic symptoms in patients when clinical and laboratory markers of HUS were improving (1,2). A second point-source outbreak caused by the same STEC O104 strain was reported in June 2011 in France (3). Both outbreaks were linked to eating fenugreek sprouts obtained from seeds produced in Egypt and distributed in Germany and other European countries (4). Instead of the attaching–effacing mechanism of adhesion to intestinal mucosa that is typical of STEC associated with severe human disease (5), the STEC O104 epidemic strain had genetic markers and an adhesion pattern (6) typical of enteroaggregative E. coli (EAEC), another group of diarrheagenic strains found frequently in developing countries (5). On basis of these findings, we reviewed our culture collection and found that an STEC strain (ED-703) from a case-patient with HUS in 2009 in Italy had the same combination of virulence factors as the strain from Germany: Stx2 production and enteroaggregative adhesion genetic markers. This strain, which had not been typed when it was isolated, showed positive PCR results for O104 (7) and H4 (8) antigen–associated genes and was agglutinated by an O104 antiserum (Statens Serum Institut, Copenhagen, Denmark). Pulsed-field gel electrophoresis showed a high degree of similarity (94.7%) with the outbreak strain from Germany (provided by M. Mielke, Robert Koch Institute, Berlin, Germany). In contrast with the outbreak strain, ED-703 did not produce extended-spectrum β-lactamases. The strain from our culture collection had been isolated from a 9-year-old girl admitted to the pediatric nephrology unit of the Ospedale Maggiore (Milan, Italy) on August 5, 2009, after 5 days of bloody diarrhea, vomiting, and abdominal pain. Diagnosis of HUS was based on the presence of hemolytic anemia, thrombocytopenia, and anuria. Neurologic symptoms (e.g., lethargy, diplopia, and nystagmus) occurred during hospitalization; magnetic resonance imaging showed signal abnormalities in the lenticular nuclei. Because of severe cardiac impairment with ejection fraction reduction and troponin increase, inotropic support and mechanical ventilation were temporarily needed. After improvement of clinical conditions, the patient was discharged, but she was readmitted a few days later because of headache, vomiting, confusion, dysarthria, hypertension, and visual impairment. Ischemic lesions were found by magnetic resonance imaging at fundus oculi. Neurologic status improved the next day, but the visual deficit persisted. Hemodialysis was needed for 2 months. Long-term sequelae of the disease were stage IV chronic kidney disease, hypertension, and severe visual impairment. Informed consent and an epidemiologic interview were obtained from the patient’s parents. The household, including her mother and 2 siblings (4 and 5 years of age), had traveled for 1 week to a resort in Tunisia; they had returned 3 weeks before the onset of the prodromal symptoms of HUS. Four days after their return, the youngest sister was hospitalized for 3 days because of bloody diarrhea, but no laboratory diagnosis was established. The mother reported having had watery diarrhea and abdominal pain on August 2. The patient history did not show any other usual risk factor for STEC infection, such as consumption of unpasteurized milk or dairy products, undercooked meat, or raw sprouts or direct exposure to ruminants or their manure. This finding suggests that the infection was probably acquired through person-to-person transmission. This case report confirms that strains of STEC O104 strictly related to the epidemic strain in Germany had already caused sporadic infections in Europe (9). Other cases have been documented in 2001 in Germany (6,9), in 2004 in France (9), and in 2010 in Finland in a patient with diarrhea who had traveled to Egypt (9). Both of the cases for which the information on the origin of the infection was available were related to travel to northern Africa, from which the seeds associated with both outbreaks could be traced (4). The history of this patient supports the hypothesis that ruminants would not have had a specific role in the transmission of STEC O104:H4, as already suggested by the epidemiologic features of the recent outbreaks (1,3). In fact, STEC O104 cannot be considered true STEC but rather EAEC strains that acquired the Stx2-coding phages by horizontal gene transfer, and EAEC is considered to be a human pathogen usually transmitted by the oral–fecal route (5). The clinical course of our patient closely resembles those of persons who had HUS associated with the German outbreak (1,2). The unusual combination of virulence factors of STEC and EAEC, already described in a group of STEC O111:H2 from an outbreak of HUS in France in 1996 (10), might confer a high degree of virulence to these strains. It also might explain the severity of the clinical findings associated with STEC O104:H4 infections.

Catheter-related infections in children treated with hemodialysis

Infectious complications of the central venous catheter (CVC) are a major source of morbidity among children treated with hemodialysis (HD), with catheter-related bloodstream infections (CRBSI) being the most important clinical manifestations. As only a few studies of children on HD have been published, the management of CVC-related infections in this population is mainly based on data derived from adults or occasionally from children not affected by end-stage renal disease (ESRD). The aim of this review is to discuss current knowledge concerning the epidemiology, prevention, and treatment of catheter-related infections in children on HD. Catheters impregnated with antibiotics/antiseptics, lock antibiotic prophylaxis, nasal mupirocin, and the application of ointments at the exit-site have all been proposed as means of reducing the risk of CVC infections, but their real efficacy in the pediatric population has not yet been demonstrated. Furthermore, it is not clear how long antibiotic therapy should be continued, and there is still debate as to whether the catheter has to be removed. We propose some practical guidelines for the management of CRBSI in children with percutaneously inserted and surgically implanted HD catheters, but a number of unresolved clinical issues still remain, which will require prospective clinical trials specifically performed in pediatric patients with ESRD.

Nutrition assessment and management in children on peritoneal dialysis

Protein-calorie malnutrition, otherwise known as cachexia, is a common problem in children undergoing chronic peritoneal dialysis (PD) and is a frequent source of significant morbidity and mortality. Recent evidence suggests that the main factors involved in the pathogenesis are metabolic acidosis, a decreased response to anabolic hormones, and chronic inflammation, associated with hormonal imbalances and an increased metabolic rate. Given the complexity and multifactorial nature of cachexia, the assessment of nutritional status in children on PD requires a complete history and physical examination; assessment of dietary intake, biochemical indices, and anthropometry; and possibly bioimpedance analysis and combined score systems. Its management should likewise be multidisciplinary and include ensuring an adequate energy and protein intake; optimal metabolic control, with the correction of acidosis, anaemia, and hyperparathyroidism; an optimal (or at least adequate) dialysis dose; and, if necessary, prescription of specific drugs such as recombinant human growth hormone.

Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin–producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored. METHODS: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted. RESULTS: Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01). CONCLUSIONS: Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.

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.

Bioimpedance analysis and cardiovascular status in pediatric patients on chronic hemodialysis

Bioimpedance analysis (BIA) is reported to be useful in assessing dry weight (DW) in patients on hemodialysis (HD), but its exact role has never been clearly defined. We reviewed our experience of using the BIA measure of reactance (Xc) in pediatric patients on chronic HD. Our approach is currently based on identifying a range of patient‐specific Xc values at which a child can be considered at DW according to a multidisciplinary assessment. Values lower than the patient‐specific limit suggests the need for a reduction in DW, whereas values higher than the limit suggest that DW should be increased. The accuracy of our approach was retrospectively assessed by analyzing the left ventricular mass index (LVMI) and the incidence of pulmonary edema (PE) in two groups: The first consisted of 13 patients (median age 15.6 years) on dialysis in 2007, before the introduction of the BIA‐based approach; the second included 18 patients (median 14.8 years) on dialysis in 2011. In 2007, three children experienced four episodes of PE, whereas no PE occurred in 2011. The median LVMI was 56.8 g/m2.7 in 2007, and 44.5 g/m2.7 in 2011 (P < 0.05). The percentage of patients with LV hypertrophy (LVMI>38.5 g/m2.7) was 92.3% in 2007 and 61.1% in 2011 (P < 0.05). There were no between‐group differences in terms of blood pressure, antihypertensive medications, percentage of symptomatic sessions, or biochemistry. In conclusion, a simple approach based on BIA may be useful in assessing DW in pediatric patients on HD, and thus improve their cardiovascular status.

A Case Study: Telemedicine Technology and Peritoneal Dialysis in Children

We investigated the feasibility and effectiveness of a telemedicine system for monitoring pediatric patients undergoing automated peritoneal dialysis (APD) at home. The system uses modem-based communication between the patients cycler and a computer in the dialysis unit, which allows data transmission and storage, and live patient-physician interaction by ISDN lines, modem, microphone with stereo speakers, and digital cameras for private video-conferencing and image capture. Two children aged 10 and 12 years, who live 1500 and 40 km from the dialysis unit, respectively, have been using the system for 7 months. All of the APD treatment data were stored and examined; 122 televisits were performed. The APD data show that both patients have complied with their dialysis prescription. The telemedicine system broadens patient/physician interchange and increases the quality of care and the life of children on peritoneal dialysis.