Clinical surveillance of thrombotic microangiopathies in Scotland, 2003-2005.

The prevalence, incidence and outcomes of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP) are not well established in adults or children from prospective studies. We sought to identify both outcomes and current management strategies using prospective, national surveillance of HUS and TTP, from 2003 to 2005 inclusive. We also investigated the links between these disorders and factors implicated in the aetiology of HUS and TTP including infections, chemotherapy, and immunosuppression. Most cases of HUS were caused by verocytotoxin-producing Escherichia coli (VTEC), of which serotype O157 predominated, although other serotypes were identified. The list of predisposing factors for TTP was more varied although use of immunosuppressive agents and severe sepsis, were the most frequent precipitants. The study demonstrates that while differentiating between HUS and TTP is sometimes difficult, in most cases the two syndromes have quite different predisposing factors and clinical parameters, enabling clinical and epidemiological profiling for these disorders.

Clinical management of children with suspected or confirmed E. coli O157 infection.

Scotland continues to report higher rates of infection with Escherichia coli O157 than elsewhere in the UK. Infection with E. coli O157 usually manifests as acute, afebrile, painful, bloody diarrhoea and is the commonest cause of Haemolytic Uraemic Syndrome (HUS), an important cause of childhood renal failure. In 1996 an outbreak of E. coli O157 infection in Central Scotland, resulted in over 500 cases and 17 deaths. Ten years on, high-profile outbreaks of E. coli O157 infection in Scotland still result in cases of HUS and fatalities. We sought to identify outcomes and describe pre-hospital clinical management strategies using prospective, national surveillance of paediatric HUS cases, from 2003 to 2006 inclusive. We recommend that children who present with acute, afebrile, and painful bloody diarrhoea be referred to hospital as early as possible for appropriate clinical management.

Neonatal nephrocalcinosis: long term follow up.

AIMS: To assess the spontaneous resolution of neonatal nephrocalcinosis and its long term effects on renal function. METHODS: Fourteen very low birthweight preterm babies with nephrocalcinosis were followed up at 5-7 years of age; 14 controls were matched for sex, gestation, and birth weight. Height, weight, blood pressure, and renal symptomatology were recorded, and a renal ultrasound scan was performed. Early morning urine osmolality and creatinine ratios of albumin, phosphate, calcium, oxalate and beta microglobulin were determined. Urea and electrolytes in the study group were determined, and glomerular filtration rate (GFR) and TmP/GFR (tubular reabsorption of phosphate per GFR) were calculated. Statistical analysis was performed on a group basis using the Mann-Whitney confidence interval. RESULTS: Mean age was 6.9 years (range 5.81-7.68). An early morning urine osmolality >700 mOsm/kg was achieved in all cases. In two cases and four controls, the calcium/creatinine ratio was >0.7 mmol/mmol. In all cases, the GFR was normal (median 132.6 ml/min/1.73 m(2) (range 104.1-173.1)). Median TmP/GFR was 1.22 mmol/l (0.73-1.61), with two having levels below the normal range. These did not have persisting nephrocalcinosis. Nephrocalcinosis was found in three of the 12 cases scanned and one control. There were no significant differences in urine biochemistry. CONCLUSIONS: Resolution of nephrocalcinosis occurred in 75% of cases. No evidence was found to suggest that nephrocalcinosis is associated with renal dysfunction in the long term. There was evidence of hypercalciuria in the cases and controls, suggesting that prematurity may be a risk factor.

Development of a high pressure liquid chromatography method for the determination of mycophenolic acid and its glucuronide metabolite in small volumes of plasma from paediatric patients.

In order to facilitate the simultaneous determination of the levels of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) in plasma samples a step wise gradient high performance liquid chromatography (HPLC) method was developed using UV detection system and naproxen as an internal standard. The analytes were extracted from plasma using Strata-X polymeric solid phase extraction (SPE) cartridges. Separation was achieved within a total chromatographic run time of 18 min at 1.0 ml/min flow rate using a Hv PURITY C18 column. The method was found to be linear over the concentration range investigated, 1.0-16 microg/ml (r > 0.99) for MPA and 10-160 microg/ml (r > 0.99) for MPAG. The limit of detection was 0.1 microg/ml for both MPAG and MPA. The intra- and inter-day imprecisions expressed as R.S.D. were 7.8 and 6.6%, respectively, for MPA (1 microg/ml) and 6.2% and 5.6%, respectively, for MPAG (20 microg/ml). The average extraction recovery from plasma was 93.06%, for MPA and 92.41% for MPAG. The method developed was found to be accurate and precise in quantifying the level of MPA and MPAG over a their therapeutic range of concentrations in small volumes of plasma and thus can be effectively used in the routine drug monitoring procedures and pharmacokinetic studies. It was also developed in such a way that it should be easily coupled to an electro-spray ionization mass spectrometer should greater sensitivity be required.

Hypercalcaemia in association with trisomy 21 (Down's syndrome).

The combination of hypercalcaemia, hypercalciuria, and nephrocalcinosis with and without renal impairment is rare in paediatric clinical practice. However, this constellation of findings has been reported in three children with trisomy 21, but the absence of detailed nutritional data has failed to clarify the underlying pathogenesis. This report describes a 4 year old girl with trisomy 21 who was found coincidentally to have hypercalcaemia, hypercalciuria, nephrocalcinosis, and renal impairment in the absence of metabolic alkalosis, following a prolonged period of excessive calcium intake.

Use of rapamycin in a transplant patient who developed cyclosporin neurotoxicity.

We describe the case of a paediatric kidney transplant patient who developed cyclosporin neurotoxicity on day 7 post-transplant. Consequently, her cyclosporin was stopped and she was commenced on rapamycin. Over the next 3 weeks her creatinine remained elevated and she had several episodes of biopsy proven rejection, despite increasing the initial dose of rapamycin by tenfold. Her whole blood rapamycin levels also remained well below the target range of 10-20 ng/ml. On day 38 post-transplant, the decision was made to add tacrolimus to her immunosuppression. At the same time, phenytoin, which had been commenced during her episode of cyclosporin neurotoxicity, was withdrawn. After this point her rapamycin blood levels rapidly increased to within the therapeutic range and she improved clinically. We propose that phenytoin, as a p450 cytochrome enzyme inducer, increased the metabolism of rapamycin in this patient and hence decreased the initial therapeutic effectiveness of this drug.

Children of renal transplant recipient mothers.

OBJECTIVE: To assess the current physical status and developmental outcome of children born to mothers following renal transplantation. METHODOLOGY: A cross-sectional prevalence survey of 48 children born to 34 women transplanted at a single centre from 1971 to 1992 was performed. Data on maternal renal disease, immunosuppression, pregnancy, delivery and child development were collected using hospital records and parental questionnaire. Children underwent physical examination, urinalysis and urinary tract ultrasound examination (US). RESULTS: Maternal renal failure was due to reflux nephropathy/chronic pyelonephritis (16), chronic glomerulonephritis (eight) and other causes (10). All mothers received prednisolone immunosuppression, as sole therapy (one), as part of triple therapy (one). Sixteen (47%) received azathioprine/prednisolone and 16 (47%) cyclosporin/prednisolone. Twenty-three girls and 25 boys aged 9 months to 18 years were studied (median age 5.2 years); 27/48 (56%) were born prematurely, 21/48 (44%) with birthweight (BW) < 2500 g 21/48 (44%) were small for gestation (BW < 10th centile). General health and physical assessment were unremarkable in 45/48 (94%) and 41/43 (95%), respectively. Development was considered normal in 47/48 (98%). Four of 40 (10%) had urinary tract abnormalities on US. CONCLUSIONS: Despite a high incidence of preterm delivery, low birth weight, intrauterine growth retardation and urinary tract abnormalities, the overall outcome for children of renal transplant recipient mothers is good.

Risk assessment of renal cortical scarring with urinary tract infection by clinical features and ultrasonography.

AIMS: To address some of the issues in the ongoing debate over the optimal diagnostic imaging following childhood urinary tract infection (UTI), by determining the risk of missing renal cortical scarring which would be detected on a technetium-99m dimercaptosuccinic acid (DMSA) gold standard if ultrasound alone were used, factoring for clinical features (upper or lower tract), UTI recurrence, and age group (infants, preschool, or school age). METHODS: Details of UTI clinical features and recurrence were recorded for 990 children with a proven UTI, and their DMSA and ultrasound results were compared for each kidney. RESULTS: The risks of missing DMSA scarring varied between 0.4% (school age children with solitary lower tract UTI) and 11.1% (infants with recurrent upper tract UTI). CONCLUSIONS: UTI clinical features are important in assessing the need for DMSA imaging. Current UK imaging guidelines are endorsed, although preschool children with solitary lower tract UTI remain a controversial group and more attention needs to focused on children with recurrent UTI.

Accuracy of clean-catch urine collection in infancy.

OBJECTIVE: To compare the accuracy of cultures of urine obtained by clean-catch urine (CCU) collection and suprapubic aspiration (SPA) in infants. DESIGN: Prospective case series undertaken in a pediatric teaching hospital and associated neonatal unit. Fifty-eight paired urine cultures (CCU collection and SPA) were obtained from 49 infants with suspected urinary tract infection. The primary outcome measure was the presence or absence of significant bacteriuria on both CCU collection and SPA; secondary outcome measures were the success of SPA with ultrasound guidance compared with aspiration without ultrasound guidance. Statistical analysis was done by using a chi(2) test. RESULTS: A false-positive rate of 5% and a false-negative rate of 12% were recorded. Sensitivity was 88.9% (95% CI 65.3-98.6), and specificity was 95.0% (95 CI% 83.1-99. 4). Ultrasound-assisted SPA was successful in 26 of 28 patients (93%) and in 13 of 21 patients (62%) when SPA was performed without ultrasound (chi(2) = 7.08, P =.008). CONCLUSIONS: We conclude that there is a good association in results of culture of urine obtained by CCU collection and SPA and would encourage the use of the CCU technique.

Abnormal IgA glycosylation in Henoch-Schönlein purpura restricted to patients with clinical nephritis.

BACKGROUND: Glomerular deposition of IgA1 is a common feature of Henoch-Schönlein purpura, and is indistinguishable from that seen in IgA nephropathy. Serum IgA1 is abnormally O-glycosylated in IgA nephropathy, and this may contribute to mesangial IgA1 deposition and the development of glomerular injury. This altered O-glycosylation of IgA1 can be detected by its increased binding to the lectin Vicia villosa. METHODS: To investigate whether IgA1 is abnormally glycosylated in Henoch-Schönlein purpura, the binding of Vicia villosa lectin to serum IgA1 was studied in the following subject groups: IgA nephropathy; adults and children with Henoch-Schönlein purpura and nephritis; children with clinically diagnosed Henoch-Schönlein purpura but no renal involvement; adults and children with non-IgA associated glomerulonephritis; and matched controls. RESULTS: The abnormality of lectin binding seen in IgA nephropathy was also found in both adults and children with Henoch-Schönlein purpura with nephritis. However, the lectin binding of serum IgA1 from children with Henoch-Schönlein purpura lacking renal involvement did not differ from controls, and similarly, no abnormality of lectin binding was seen in patients with non-IgA associated glomerulonephritis. CONCLUSIONS: These data indicate that the abnormality of IgA1 O-glycosylation seen in IgA nephropathy is also found in Henoch-Schönlein purpura, but only in those subjects with renal involvement, while IgA1 O-glycosylation is normal in patients with other forms of renal disease. These findings lend strong support to a role for altered IgA1 O-glycosylation in the pathogenesis of IgA-associated glomerular disease.

Complement activation in Henoch-Schönlein purpura.

The pathogenetic mechanism underlying Henoch-Schönlein purpura (HSP) is poorly understood. Complement activation has been thought to have a role, but despite the demonstration of complement components in skin and renal biopsy material, serological evidence of complement activation is not convincing. We have assessed complement activation in 64 children with acute HSP. We used an enzyme-linked immunosorbent assay to measure plasma levels of three multimolecular complement activation protein (CAP) complexes: C1r:C1s:C1-inhibitor, C3bP and C5b-9. We found no significant difference between the levels of CAPs in children with acute HSP and a control group of children. This study does not support a role for complement activation in the pathogenesis of HSP.

Craniosynostosis in X-linked hypophosphataemic rickets.

A report of three cases of craniosynostosis in X-linked hypophosphataemic rickets (XLH) is presented. The literature is reviewed, suggesting that craniosynostosis is relatively common in XLH and that boys may be more at risk than girls. It is recommended that radiological screening be offered to all patients with XLH.

The neutrophil oxidative burst in diarrhoea-associated haemolytic uraemic syndrome.

Neutrophil-mediated tissue damage has been implicated in the pathogenesis of diarrhoea-associated haemolytic uraemic syndrome (D+ HUS). This study evaluates priming and activation of the neutrophil oxidative burst in D+ HUS using chemiluminescent techniques. Peripheral blood neutrophils from 11 children with acute D+ HUS were examined. No difference was found in the oxidative burst of neutrophils from patients and controls. Serum elastase levels were measured in 8 patients and found to be significantly elevated. Although elastase results suggest neutrophil activation, chemiluminescence studies do not confirm this in the peripheral blood neutrophil. This does not support a significant role for circulating agents in priming and activating the peripheral blood neutrophil.

Hypophosphatasia.

Hypophosphatasia is a rare inherited metabolic disease characterised by reduced plasma and tissue alkaline phosphatase activity, and may present in infancy, childhood or adulthood. The differing modes of inheritance, presentation and natural history are likely to reflect variable expression of the alkaline phosphatase gene defect. A case of infantile hypophophatasia presenting with hypercalcaemia is described and the histological and radiological resolution of the mineralisation defect present initially are reported.

Hypomagnesaemic tetany.

Hypomagnesaemic tetany (hypomagnesaemic tetany with secondary hypocalcaemia) is a rare inherited form of hypomagnesaemia. Initial reports involved affected males only; however, affected females have also been reported. The case of a child with hypomagnesaemic tetany is described, the biochemical and genetic aspects of this condition are reviewed and the importance of the assessment of renal magnesium excretion in patients presenting with hypomagnesaemia is highlighted.