Ekkehard Ring

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES Atypical hemolytic uremic syndrome (aHUS) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage. Eculizumab, a humanized mAb against complement protein C5, inhibits activation of the terminal complement pathway. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We report an adolescent with relapsing unclassified aHUS. On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started. Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk. Subsequently, plasma exchanges (three times per week) failed to prevent ongoing aHUS activity and progressive renal failure. After 12 wk, aHUS treatment was switched to eculizumab. RESULTS Eculizumab was effective in terminating the microangiopathic hemolytic process in two aHUS relapses; however, after normalization of complement activity, aHUS recurred and ultimately led to anuric end-stage renal failure. CONCLUSIONS In this patient, complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity. Nevertheless, renal damage as a result of preceding and subsequent aHUS activity resulted in end-stage renal failure; therefore, therapeutic success may depend on early administration of eculizumab. The optimal duration of treatment may be variable and remains to be determined.

Successful treatment of chronic recurrent multifocal osteomyelitis with tumor necrosis factor-alpha blockage.

We describe the case of an 18-year-old girl with chronic recurrent multifocal osteomyelitis (CRMO) over a period of 10 years. She had suffered predominantly from very painful recurrent swelling of her cheeks. Various therapeutic regimens including nonsteroidal antiinflammatory drugs and steroids had shown only a partial or temporary response. Because tumor necrosis factor-α–blocking agents have been successfully applied in Crohns-associated CRMO and the related SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, tumor necrosis factor-α–blocking therapy with infliximab was initiated. Thereafter, apart from 1 mild episode, no additional recurrences were observed during 21 months of follow-up. Infliximab was well tolerated, and steroids were tapered off. Our observation indicates that infliximab may be an effective therapeutic option in CRMO.

Five years experience with continuous extracorporeal renal support in paediatric intensive care

Continuous arterio-venous haemofiltration (CAVH) and continuous veno-venous haemofiltration (CVVH) were used as renal support in 52 critically ill infants and children with acute renal failure. The majority of the patients were on mechanical ventilation (90%) and needed vasopressor support (85%). Uraemia was satisfactorily controlled with both treatment modes. Post-treatment serum urea levels were not different between survivors (94±8.8 mg/dl) and non-survivors (99.5±8.8 mg/dl). There were significant differences between survivors and non-survivors in the mean arterial pressure (64.7±3.8 vs 48.0±2.2 mmHg,p<0.001), the number of organ system failures (2.9±0.16 vs 3.8±0.21,p<0.025), and the severity of illness assessed by the acute physiologic score for children (APSC 19.4±1.9 vs 26.3±1.9,p<0.01). The overall mortality was 48%. The mortality in the CVVH group (65%) was higher than in the CAVH group (40%). Death was significantly related to sepsis (p<0.005) and multiple system organ failure (p<0.005). A major complication during CAVH was one femoral artery thrombosis after 12 days of treatment. Technical problems were only observed during CVVH. CAVH and CVVH are safe and effective methods of continuous renal support for critically ill paediatric patients with multiple system organ failure. CAVH is simpler, needs no specially trained staff and seems to the ideal renal replacement system for critically ill infants.

De novo HNF-1β gene mutation in familial hypoplastic glomerulocystic kidney disease

Abstract. Mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1β are associated with maturity-onset diabetes of the young (type V), non-diabetic renal disease, and occasionally genital malformations in females. Recently, familial hypoplastic glomerulocystic kidney disease (GCKD) has been added to the clinical spectrum of HNF-1β gene mutations. Familial hypoplastic GCKD is a rare, dominantly inherited disorder characterized by small kidneys containing glomerular cysts, abnormal pelvicalyceal anatomy, and chronic renal failure. A family with hypoplastic GCKD occurring in the father and the daughter was screened for mutations in the HNF-1β gene. The sequence of exon 4 of the HNF-1β gene revealed a C insertion at codon 334 resulting in a frameshift mutation (P334fsinsC) in two family members. The P334fsinsC allele co-segregated with hypoplastic GCKD in the family. Oral glucose tolerance testing was normal in the 11-year-old girl. In her 38-year-old father, impaired glucose tolerance was detected. These studies provide further evidence that familial hypoplastic GCKD is associated with HNF-1β gene mutations. HNF-1β gene mutation screening may prove useful in patients with small cystic kidneys and chronic renal failure, in whom a definite renal diagnosis could otherwise only be established by renal biopsy.

Anticoagulation for Continuous Arteriovenous Hemofiltration in Children

Continuous arteriovenous hemofiltration requires continuous anticoagulation to prevent early hemofilter clotting. We used heparin given continuously in the arterial line of the extracorporeal circuit as anticoagulant in children with initially normal coagulation status, and heparin and/or prostacyclin in high-risk bleeding patients with preexisting coagulopathy. Heparin infusion enabled a mean running time of 22.2 +/- 9.6 h, with the 0.1-m2 hemofilter and of 26.6 +/- 4.7 h with the 0.25-m2 hemofilter. The mean filter running time with combined heparin/prostacyclin infusion was 31 +/- 8.8 h. Prostacyclin as the sole antithrombotic agent provided good filter function only in 1 patient with preexisting coagulopathy. No adverse effects such as bleeding thrombosis, or hypotension were observed.

Amplitude coded-colour Doppler sonography in paediatric renal disease.

Abstract The aim of our study was to assess the ability of amplitude coded-colour Doppler sonography (ACDS) to depict altered perfusion in paediatric renal disease in a prospective study. Colour Doppler sonography (CDS) and ACDS examinations were performed in 180 renal units (90 patients; age range newborn to 16 years) with unilateral or bilateral renal disease (e. g. reflux nephropathy, renal scars, end-stage renal disease, ureteropelvic junction obstruction, urinary tract infection, renal failure, haemolytic uraemic syndrome, nephrotic syndrome, systemic lupus erythematosus (LE), renal biopsy, congenital dysplasia, tumour/infiltration). The ACDS results were compared with scintigraphy or CT as well as to clinical findings. Amplitude colour-coded Doppler sonography accurately demonstrated normal vasculature in 49 of 51 healthy kidneys ( = 96 %); 3 healthy kidneys could not be evaluated due to motion/artefacts. In 39 of 43 kidneys with focally altered perfusion ACDS could be performed and correctly depicted focally impaired vasculature/perfusion in 35 kidneys ( = 89.7 %). Seventy-three of 83 kidneys with diffusely impaired perfusion could be evaluated by ACDS and altered pattern was correctly depicted in 58 kidneys ( = 79.4 %), with an overall percentage of agreement of 87.1 %. Amplitude CDS appears to be useful in infants and children. Compared with CDS it improves visualisation of especially focally impaired vasculature/perfusion and should be considered a valuable adjunct to conventional investigations.

Continuous arteriovenous hemofiltration in premature infants

Five critically ill premature infants with acute renal failure (ARF) and hypervolemia were treated by continuous arteriovenous hemofiltration (CAVH). Prostacyclin was used to prevent hemofilter clotting. Mean treatment duration was 53.6 +/- 14 h. Mean blood flow rates of 1.6 +/- 0.22 ml/min and filtration fractions of 17.2 +/- 3.7% produced mean ultrafiltration rates of 8.3 +/- 3.1 ml/kg.h. Fluid overload was easily corrected by means of CAVH. The mean prehemofiltration serum creatinine and urea levels were 2.3 +/- 0.4 and 77 +/- 29.7 mg/dl; the mean posthemofiltration levels were 2.38 +/- 0.43 and 92 +/- 34.4 mg/dl, respectively. Hemofilter clotting occurred every 14 h. Urinary output was restored in three infants. Three of the five infants died, but none of the deaths was related to ARF or CAVH. CAVH is a safe and simple method to control fluid and metabolic imbalances in critically ill premature infants.

Continuous arteriovenous renal replacement systems for critically ill children

Five different arteriovenous renal replacement systems were used to treat 23 critically ill oliguric or anuric children. Slow continuous ultrafiltration (SCU) was carried out for 8 patient days, continuous arteriovenous haemofiltration (CAVH) for 40, suction-supported CAVH for 56, continuous or intermittent arteriovenous haemodiafiltration (AVHDF) for 3, and continuous arteriovenous haemodialysis (CAVHD) for 24 days. SCU allowed excellent control of fluid overload in 4 patients within 47±17 h. Urea clearances ranged from 5.6±2.1 ml/min per m2 (spontaneous CAVH) to 15.3±3.7 ml/min per m2 (CAVHD) and enabled good control of azotaemia. Ultrafiltration rates of the different filters ranged from 1.6±0.3 to 11.5±2.4 ml/min per m2. The only serious complication was a femoral artery thrombosis in a 1.5-year-old boy. Minor side-effects were local bleeding at the entrance site of the arterial catheter and transient hypotension during suction-supported CAVH. Of 23 patients, 8 died because of progressive multiple organ system failure, a mortality of 35%.

Value of comprehensive renal ultrasound in children with acute urinary tract infection for assessment of renal involvement: comparison with DMSA scintigraphy and final diagnosis

The aim of this study was to evaluate the value of comprehensive renal ultrasound (US), i.e., combining greyscale US and amplitude-coded color Doppler sonography (aCDS), for assessment of urinary tract infection (UTI) in infants and children, compared to (1) 99mTc DMSA scintigraphy and (2) final diagnosis. Two hundred eighty-seven children with UTI underwent renal comprehensive US and DMSA scintigraphy. The results were compared with regard to their reliability to diagnose renal involvement, using (1) DMSA scintigraphy and (2) final diagnosis as the gold standard. Sixty-seven children clinically had renal involvement. Sensitivity increased from 84.1% using only aCDS to 92.1% for the combined US approach, using DMSA scintigraphy as the reference standard. When correlated with the final diagnosis, sensitivity for DMSA scintigraphy was 92.5%; sensitivity for comprehensive US was 94.0%. Our data demonstrate an increasing sensitivity using the combination of renal greyscale US supplemented by aCDS for differentiation of upper from lower UTI. Sensitivity for DMSA and comprehensive US was similar for both methods compared to the final diagnosis. Comprehensive US should gain a more important role in the imaging algorithm of children with acute UTI, thereby reducing the radiation burden.

Three-Dimensional Ultrasonography-Based Virtual Cystoscopy of the Pediatric Urinary Bladder A Preliminary Report on Feasibility and Potential Value

Objective. The purpose of this study was to validate the feasibility and potential of 3‐dimensional ultrasonography (3DUS)‐based virtual cystoscopy in the pediatric urinary bladder. Methods. Twenty patients (age range, newborn–14 years) underwent urinary tract ultrasonography and 3DUS of the urinary bladder. From this data set, virtual cystoscopy was reconstructed for visualization of the inner bladder surface. Three‐dimensional ultrasonography was compared with 2‐dimensional ultrasonographic (2DUS) findings, voiding cystourethrography (VCUG) results, and reports from cystoscopy or surgery when available. Results. Three‐dimensional ultrasonography was feasible in all patients. Data quality was sufficient for virtual cystoscopy without major motion artifacts. The 3DUS results matched all other findings; particularly, 3DUS superiorly visualized the ureteral ostium and the bladder neck configuration; in 5 patients, 3DUS depicted pathologically shaped ostia not detected by 2DUS. This correlated with the presence of vesicoureteral reflux on VCUG. Performing virtual cystoscopy added 1 minute to the investigation time (range, 0.5–2 minutes) and 3 minutes for postprocessing and viewing (range, 2–5 minutes). Conclusions. Three‐dimensional ultrasonography‐based virtual cystoscopy is feasible in the pediatric urinary bladder without sedation. It reveals surface information not accessible by 2DUS, improving detection of pathologic conditions such as atypically shaped ureteral ostia. Three‐dimensional ultrasonography‐based cystoscopy may become a valuable adjunct to 2DUS of the pediatric urinary tract, improving selection criteria for further imaging such as VCUG, and potentially may help reduce the need for endoscopic cystoscopy. However, these preliminary results still have to be confirmed in prospective studies with larger patient numbers.