Sara Testa

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.

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS.

Reduced Systolic Myocardial Function in Children with Chronic Renal Insufficiency

Increased left ventricular (LV) mass in children with chronic renal insufficiency (CRI) might be adaptive to sustain myocardial performance in the presence of increased loading conditions. It was hypothesized that in children with CRI, LV systolic function is impaired despite increased LV mass (LVM). Standard echocardiograms were obtained in 130 predialysis children who were aged 3 to 18 yr (59% boys) and had stages II through IV chronic kidney disease and in 130 healthy children of similar age, gender distribution, and body build. Systolic function was assessed by measurement of fractional shortening at the endocardial (eS) and midwall (mS) levels and computation of end-systolic stress (myocardial afterload). The patients with CRI exhibited a 6% lower eS (33.1 +/- 5.5 versus 35.3 +/- 6.1%; P < 0.05) and 10% lower mS (17.8 +/- 3.1 versus 19.7 +/- 2.7%; P < 0.001) than control subjects in the presence of significantly elevated BP, increased LVM, and more concentric LV geometry. Whereas the decreased eS was explained entirely by augmented end-systolic stress, mS remained reduced after correction for myocardial afterload. The prevalence of subclinical systolic dysfunction as defined by impaired mS was more than five-fold higher in patients with CRI compared with control subjects (24.6 versus 4.5%; P < 0.001). Systolic dysfunction was most common (48%) in patients with concentric hypertrophy and associated with lower hemoglobin levels. CRI in children is associated with impaired intrinsic LV contractility, which parallels increased LVM.

Gram-Negative Peritonitis in Children Undergoing Long-term Peritoneal Dialysis

BACKGROUND The proportion of gram-negative causative organisms in peritoneal dialysis-associated peritonitis is increasing. Little published information for this complication exists in children. The objective of this study is to evaluate the clinical presentation, early and late response to treatment, and identification of factors influencing the outcome of gram-negative peritonitis (GNP) in children. STUDY DESIGN Case series. SETTING AND PARTICIPANTS 104 children (aged 7.9 +/- 5.9 years) with 121 GNP episodes reported to the International Pediatric Peritonitis Registry from October 2001 through December 2004. PREDICTORS Patient, clinical, bacteriological, and treatment features. OUTCOMES Initial response to empirical treatment was assessed after approximately 72 hours of therapy. Final outcome was judged according to the occurrence of death, technique failure, relapse, need for catheter exchange, and a composite end point defining full functional recovery. RESULTS 44% of episodes of GNP occurred in children younger than 5 years. Causative organisms included Pseudomonas species, 21%; Klebsiella species, 18%; Escherichia coli, 17%; and Acinetobacter species, 12%. Thirty-two percent of organisms classified as gram-negative were not identified further. Clinical manifestations were severe and uniform for all causative gram-negative agents. A substantial proportion (20%) of organisms were resistant to ceftazidime, with resulting suboptimal response to empirical therapy. By day 3 of initial empiric treatment, 85% of children with GNP had improved clinically (39%, complete resolution; 46%, improvement in symptoms), 10% showed poor response, and 5% had worsening of symptoms. Multivariate analysis identified severe abdominal pain, use of a single-cuff catheter, and intermittent (versus continuous) intraperitoneal ceftazidime administration as independent predictors of worse initial response to treatment. Full functional recovery was achieved in 86% of episodes. Nineteen patients (16%) required catheter removal, 11 (9%) experienced a relapse, 7 (6%) discontinued peritoneal dialysis therapy permanently, and 3 died. Lack of clinical improvement after 72 hours of therapy (odds ratio, 5.39; P < 0.01) and the presence of an exit-site infection (odds ratio, 7.69; P = 0.01) independently increased the risk of an incomplete functional recovery. LIMITATIONS The study was not designed to assess absolute incidence figures or risk factors for the development of GNP in children. CONCLUSIONS GNP is a significant complication of long-term peritoneal dialysis therapy in children, and a substantial proportion of affected children are at risk of permanent sequelae. Because results of empiric treatment with ceftazidime are suboptimal in the setting of this infection, alternative antimicrobial agents should be reconsidered.

Calcitriol pulse therapy is not more effective than daily calcitriol therapy in controlling secondary hyperparathyroidism in children with chronic renal failure

Abstract Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism, but its efficacy and safety are still under discussion. The present randomized multicenter study compares the effect of an 8-week course of daily versus intermittent (twice weekly) calcitriol therapy on parathyroid hormone (PTH) suppression in 59 children (mean age 8.4±4.7 years) with chronic renal insufficiency (mean Ccr 22.4±11.6 ml/min per 1.73 m2) and secondary hyperparathyroidism. After a 3-week washout period, the patients were randomly assigned to treatment with daily oral calcitriol (10 ng/kg per day) or intermittent oral calcitriol (35 ng/kg given twice a week). The calcitriol dose was not changed throughout the study period of 8 weeks. At start of the study, the median intact PTH (iPTH) level was 485 pg/ml (range 83–2032) in the daily group (n=29) and 315 pg/ml (range 93–1638) in the intermittent group (n=30). After 8 weeks, the respective median iPTH concentrations were 232 pg/ml (range 63–1614) and 218 pg/ml (range 2–1785) (ns). The mean iPTH decrease from baseline was 19.2±57.8% and 13.7±46.7% respectively (not significant). Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group. One episode of hypercalcemia (>11.5 mg/dl) was observed in both groups and a single episode of hyperphosphatemia (>7.5 mg/dl) was observed in the daily group. It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis.

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.

Differences between office and ambulatory blood pressures in children and adolescents attending a hospital hypertension clinic.

Background and objectives: Information on ambulatory blood pressure monitoring (ABPM) in children is scarce. While in adults office BP (OBP) is higher than ABP and the difference increases as OBP increases, information in children suggests that at this young age ABP is no lower and often higher than OBP. This study was aimed at describing OBP–ABP differences in a cohort of children of different ages and BPs, and investigating whether OBP–ABP differences are dependent on age or OBP level. Methods: We retrospectively compared OBP and 24-h, daytime and night-time ABP in 433 children and adolescents aged 4–18 years, referred to our hospital clinic. Results: OBP was found to be significantly lower than 24-h and daytime ABP in the low age tertile (4–10 years) but not in the medium and high tertiles. OBP was also lower than ABP in normotensive patients (n = 182), but higher than ABP in untreated hypertensive patients (n = 92) despite similar ages. Continuous analyses showed a weak correlation of OBP–ABP differences with age, and a much stronger correlation with OBP so that 24-h ABP was higher than OBP at OBP values less than 117/73 mmHg and lower than OBP at higher OBP values. Logistic regression analysis indicates that also in children OBP accounts for most of the OBP–ABP difference. Conclusion: There is a common relation both in children and adults between OBP and ABP. It is only because high OBP is common in the elderly, and the lowest OBP is usually found in young children that large positive OBP–ABP differences have been associated with old age, and negative differences with childhood. OBP–ABP differences, often defined as white-coat effect, can have different directions and are likely to be largely due to regression to the mean.

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.

Skin Involvement in Atypical Hemolytic Uremic Syndrome

Skin involvement in atypical hemolytic uremic syndrome (aHUS) is very uncommon and therefore often unrecognized as a specific symptom of aHUS. We describe 3 cases of patients with aHUS who developed skin lesions that completely recovered when disease-specific treatment was established. These cases suggest that in individuals with aHUS, when skin lesions of unknown origin occur, the possibility that they are due to thrombotic microangiopathy should be considered.