Maria Herthelius

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome

BACKGROUND Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

The Swedish Reflux Trial in Children: III. Urinary Tract Infection Pattern

PURPOSE We evaluated the difference in the febrile urinary tract infection rate in small children with dilating vesicoureteral reflux randomly allocated to 3 management alternatives, including antibiotic prophylaxis, endoscopic treatment or surveillance only as the control. MATERIALS AND METHODS At 23 centers a total of 203 children were included in the study, including 128 girls and 75 boys 1 to younger than 2 years. Vesicoureteral reflux grade III in 126 cases and IV in 77 was detected after a febrile urinary tract infection (194) after prenatal screening (9). Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done before randomization and after 2 years. The febrile urinary tract infection rate was analyzed by the intent to treat principle. RESULTS We noted a total of 67 febrile recurrences in 42 girls and a total of 8 in 7 boys (p = 0.0001). There was a difference in the recurrence rate among treatment groups in girls with febrile infection in 8 of 43 (19%) on prophylaxis, 10 of 43 (23%) with endoscopic therapy and 24 of 42 (57%) on surveillance (p = 0.0002). In girls the recurrence rate was associated with persistent reflux after 2 years (p = 0.0095). However, reflux severity (grade III or IV) at study entry did not predict recurrence. CONCLUSIONS In this randomized, controlled trial there was a high rate of recurrent febrile urinary tract infection in girls older than 1 year with dilating vesicoureteral reflux at study entry but not in boys. Antibiotic prophylaxis and endoscopic treatment decreased the infection rate.

Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics

PURPOSE We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection. MATERIALS AND METHODS Children 1 to younger than 2 years with grade III-IV reflux were recruited into this prospective, open, randomized, controlled, multicenter study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercapto-succinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle. RESULTS During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy. CONCLUSIONS Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions.

Comparison of Plasma Clearance of Iohexol and Urinary Clearance of Inulin for Measurement of GFR in Children

BACKGROUND Very few studies have been published that compare plasma clearance of iohexol (Cio) with renal clearance of inulin (Cin). STUDY DESIGN Diagnostic test study. SETTING & PARTICIPANTS 60 children aged 11.6 ± 4.5 years with different kidney disorders were investigated. INDEX TEST Plasma Cio calculated from the slope and a single point. REFERENCE TEST Renal Cin with continuous infusion during water diuresis. Results were compared with the correlation coefficients, bias and precision, accuracy percentage, root mean square error, and intraclass correlation. OTHER MEASUREMENTS Measured creatinine clearance and estimated glomerular filtration rate based on serum creatinine level and height. RESULTS Mean Cin was 70.7 ± 41.3 (SD) mL/min/1.73 m². Mean differences between Cio and Cin were 2.65 and 2.00 mL/min/1.73 m² for the slope and single-point methods, respectively. Precision was ±16 mL/min/1.73 m² and intraclass correlation was 0.92 in both methods. Proportions of Cio within 30% of Cin were 83.3% and 86.7% for the slope and single-point methods, respectively. LIMITATIONS A limited number of patients; no adults were studied. CONCLUSIONS Plasma Cio shows good agreement with renal Cin.

Schwartz Formula: Is One k-Coefficient Adequate for All Children?

Background/Objective Plasma-creatinine-based equations to estimate the glomerular filtration rate are recommended by several clinical guidelines. In 2009, Schwartz et al. adapted the traditional Schwartz equation to children and adolescents but did not find different k-coefficients between children and adolescents (k = 36.5 for all patients). We reevaluated the coefficient of the 2009-Schwartz formula according to sex and age in a pediatric population. Patients/Methods We used linear mixed-effects models to reestimate the 2009-Schwartz k-coefficient in 360 consecutive French subjects aged 1 to 18 years referred to a single centre between July 2003 and July 2010 (965 measurements). We assessed the agreement between the estimated glomerular filtration rate obtained with the new formula (called Schwartz-Lyon) and the rate measured by inulin clearance. We then compared this agreement to the one between the measured glomerular filtration rate and 2009-Schwartz formula, first in the French then in a Swedish cohort. Results In Schwartz-Lyon formula, k was estimated at 32.5 in boys <13 years and all girls and at 36.5 in boys aged ≥13 years. The performance of this formula was higher than that of 2009-Schwartz formula in children <13 years. This was first supported by a statistically significant reduction of the overestimation of the measured glomerular filtration rate in both cohorts, by better 10% and 30% accuracies, and by a better concordance correlation coefficient. Conclusions The performance and simplicity of Schwartz formula are strong arguments for its routine use in children and adolescents. The specific coefficient for children aged <13 years further improves this performance.

Bladder dysfunction in children and adolescents after renal transplantation

The underlying mechanisms of urinary-tract infections (UTI) in renal transplant recipients are still not fully understood. In otherwise healthy children, bladder dysfunction increases the susceptibility to UTI. The aim of this study was to evaluate lower-urinary-tract function in children and adolescents after renal transplantation. Sixty-eight recipients of renal transplants, 5–20 years of age and 1–15 years after transplantation, were evaluated for their bladder function with a questionnaire, uroflowmetry and bladder ultrasound, and for renal function (glomerular filtration rate) by measuring clearance of inulin or iohexol. Forty-nine patients (72%) had some type of abnormality of bladder function. Abnormal bladder capacity was found in 26%, abnormal urinary flow in 50% and residual urine in 32% of the patients. There was no significant difference in bladder or renal function in children with urinary-tract malformations compared with those with normal urinary tract. Furthermore, there was no significant difference in renal function in patients with bladder dysfunction compared with those without. The incidence of bladder dysfunction is high in children and adolescents after renal transplantation, but the clinical significance of this finding and whether there is a correlation between bladder dysfunction and UTI in these patients need to be clarified further.

Lower Urinary Tract Symptoms in Children and Adolescents With Chronic Renal Failure

PURPOSE Lower urinary tract symptoms are common in children after renal transplantation. However, it is unclear whether lower urinary tract symptoms are present before transplantation or appear postoperatively. We sought to evaluate bladder function in children before renal transplantation. MATERIALS AND METHODS A total of 40 children 5 to 18 years old with a glomerular filtration rate of less than 50 ml per minute per 1.73 m(2) were consecutively enrolled in the study from 2006 to 2008. Bladder function was assessed by a comprehensive history, bladder diary, uroflowmetry and bladder ultrasound. RESULTS Of the patients 20% suffered from incontinence, 47.5% had bladder capacity larger than expected for age, 20% had discontinuous flow and 15% had residual urine 20 ml or greater. Signs consistent with bladder dysfunction (incontinence, abnormal bladder capacity, discontinuous urinary flow and/or residual urine) were observed in 13 of 13 children (100%) with urological disorders and 16 of 27 (59%) with nonurological disorders. Polyuria was present in 39% of the patients. Prior febrile urinary tract infection was significantly more common in children with vs without signs of bladder dysfunction. CONCLUSIONS Lower urinary tract symptoms are common in children with chronic renal failure. Screening for bladder dysfunction is important not only in children with urological disorders, but also in those with nonurological disorders, so that dysfunction can be corrected before transplantation.

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli-Infected Mice.

Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.

Minoxidil therapy in children and young adult patients with renal disease and refractory hypertension: value when multidrug regimens have failed to achieve blood pressure control.

Minoxidil therapy in children and young adult patients with renal disease and refractory hypertension: value when multidrug regimens have failed to achieve blood pressure control