A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

Public health implications of a case of haemolytic-uraemic syndrome associated with a concomitant outbreak of mild gastroenteritis in a small rural community.

The concomitant occurrence of a case of haemolytic-uraemic syndrome (HUS) and 62 cases of mild gastroenteritis in schools of a small rural community in southern Italy induced the health authorities to suspect a foodborne outbreak of shiga-toxin-producing Escherichia coli (STEC) infection. The schools were closed and the catering service involved was investigated. However, STEC were not isolated from the HUS case or from the 56 cases of gastroenteritis examined, and the HUS case and the outbreak of gastroenteritis were probably just coincidental. A retrospective cohort study failed to show any correlation with consumption of school meals and suggested that the outbreak probably started outside the school setting and then spread within the schools by person-to-person transmission. All the cases examined were negative for common enteric pathogens and the responsible agent for the cases of gastroenteritis was not identified. The concern raised in the small community by the occurrence of a severe case of HUS and the lack of a rapid epidemiological assessment excluding the occurrence of a STEC outbreak, turned an epidemic episode of mild gastroenteritis into a public health emergency with relevant socioeconomic consequences. Prompt intervention in outbreaks following timely and effective risk communication are crucial for taking the most appropriate control measures and avoiding the spread of fear and panic in the community.

Increased NO production in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mutation of the SLC7A7 gene characterized by renal failure, pulmonary alveolar proteinosis, lupus-like autoimmune symptoms and usually increased plasma citrulline. In order to better understand the underlying mechanism, we studied the plasma and urinary nitrite/nitrate (NO2-/NO3-) concentrations in three LPI patients and the in vitro NO2- production in cultured fibroblasts. Our data show that NO3- levels are increased in the plasma of patients with LPI. Similarly, NO2- release in the medium of cultured fibroblasts was increased. On this basis, we hypothesize that some of the poorly understood clinical signs of LPI could be related to the activation of the NO-citrulline pathway.

Predictive risk factors for chronic renal failure in primary high-grade vesico-ureteric reflux.

OBJECTIVE: To evaluate and define the risk factors predictive of chronic renal failure (CRF) in children with severe bilateral primary vesico-ureteric reflux (VUR), observed within the first year of life and with a long follow-up. PATIENTS AND METHODS: The study comprised 50 patients presenting with grade 3-5 bilateral VUR diagnosed in the first year of life; 12 were suspected prenatally and confirmed shortly after birth, before any urinary tract infection (UTI). The mean (range) follow-up was 6.3 (1-16) years. The variables considered within the first year of life were: gender, prenatal diagnosis with no UTI, number of febrile UTIs, serum creatinine and urea nitrogen levels, metabolic acidosis, proteinuria, 24-h urine output, hypertension, bilateral renal length on ultrasonography and renal scarring on renal scintigraphy. CRF was defined as a creatinine clearance of <80 mL/min/1.73 m(2) at the last follow-up. The results were assessed using univariate and multivariate analyses (backward-stepwise multiple regression) of the selected variables. RESULTS: CRF was detected at the last follow-up in 27 patients (54%), all boys, while renal function was normal in 23 (46%; seven girls). None of the 12 patients with prenatal diagnosis had UTI, but six had CRF. Febrile UTI was the presenting symptom in 38 (76%) patients and 17 (34%) of them had renal scarring. There was no significant difference between the prenatally detected VUR and febrile UTI group in the outcome as CRF. The univariate and multiple regression analysis showed that the first serum creatinine threshold of >6 mg/L before 1 year old was the most significant risk factor for CRF (P < 0.001; odds ratio 1.25). CONCLUSIONS: Children with primary bilateral high-grade VUR and a serum creatinine of > 6 mg/L in the first year of life have a significant risk of developing CRF in the long-term. Prenatal diagnosis and postnatal febrile UTI do not modify the outcome for renal function.

Renal hemodynamic effect of tacrolimus in renal transplanted children.

Like cyclosporine (CsA), tacrolimus acts through the inhibition of renal phosphatase calcineurin. CsA induces reversible vasoconstriction, causing a transient reduction of renal plasma flow in patients with renal transplantation. The aim of this study was to determine the effect of tacrolimus on renal plasma flow in renal transplanted children. Eight children were studied with a median age of 10.6 years, a mean glomerular filtration rate (inulin clearance) of 55 ml/min per 1.73 m2 (range 29-95), and a mean follow-up after transplantation of 5.6 months. Effective renal plasma flow (ERPF) was studied in each patient for 12 h after tacrolimus administration. Clearances were obtained every 2 h for 12 h after drug administration. Tacrolimus pharmacokinetics was also studied. Average ERPF at the start of the test was 289 ml/min per 1.73 m2 (range 177-404, SD +/- 106). Variation in each of the 2-h periods was not significant, although a mild reduction of plasma flow was observed in three of the eight children. No correlation was found between tacrolimus AUC, peak, or trough levels and renal blood flow variations. Despite the relatively small number of patients studied, these data suggest that, in vivo, a therapeutic oral dose of tacrolimus is not necessarily followed by a significant reduction of ERPF in renal transplanted children.

Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators.

We investigated the prognostic indicators in ten hyperammonemic neonates: four treated by continuous arteriovenous hemodialysis (CAVHD), four with continuous venovenous hemodialysis (CVVHD), and two with hemodialysis (HD). Plasma ammonium levels decreased significantly within the first 24 h irrespective of dialysis modality (from 1419 to 114 micromol/l, median values; P<0.0001). CVVHD achieved the highest ammonium clearance. HD provided highest ammonium extraction but clearance was hampered by severe hemodynamic instability. Five patients had a good outcome (normal at follow-up of 9-59 months), five had poor outcome (four died and one has severe neurological damage). Total coma duration was shorter in patients who had a good outcome (47+/-11 vs 78+/-13 h; P=0.02). Remarkably, only coma duration before dialysis determined this difference (22.2+/-10.1 vs 48.8+/-11.2 h; P=0.02). In cases with good outcome, coma duration was <33 h, whereas the others exceeded this limit. The prognosis was not related to dialysis modality, rapidity in reducing ammonium levels or to the underlying metabolic defect. In conclusion, results showed CVVHD to be the optimal modality for extracorporeal ammonium detoxification. However, the most relevant indicator for prognosis was coma duration before the start of dialysis. Therefore, major efforts should be made to refer patients quickly to highly specialized centers.

Acquired glomerulocystic kidney disease following hemolytic uremic syndrome.

Glomerulocystic kidney disease (GCKD) is a rare congenital condition that is usually reported in infants and young children. Only five cases of acquired GCKD after an acquired renal disease have been reported. Among these, two patients have developed cystic glomerular lesions following hemolytic uremic syndrome (HUS). We report a third case in a 2-year-old patient with this association. Common features between these three cases include atypical HUS, development of GCKD after prolonged peritoneal dialysis treatment, severe hypertension, and normal-sized kidneys without development of macroscopic cysts. Pathology findings in our patient include heavy expression of epidermal growth factor receptor in proximal tubules and evidence of obstruction of the glomerular outflow. We speculate that cystic dilatation of the Bowman's capsule may be secondary to ischemic lesions leading to proximal tubular obstruction.

Distribution of alpha-chains of type IV collagen in glomerular basement membranes with ultrastructural alterations suggestive of Alport syndrome.

BACKGROUND: In Alport syndrome (AS) impaired production and/or assembly of col IV alpha-chain isoforms results in abnormal structure of glomerular basement membrane (GBM), haematuria and, frequently, progressive renal disease. We investigated the relationship between col IV alpha-chains expression and morphology of GBM, as a possible key to the better understanding of the pathogenesis of renal disease in AS. METHODS: GBM distribution of col IV alpha1-, alpha3-, and alpha5-chain was investigated by immunohistochemistry in 32 patients (21 males and 11 females, mean age at biopsy of 11.5 years) with ultrastructural findings suggestive of AS. Ten patients had a proven COL4A5 mutation. Based on the severity of ultrastructural findings, the biopsies were grouped in three (I-III) electron microscopy (EM) classes. Significant EM changes of GBM (thinning, thickening, splitting, basket weaving of the lamina densa) were singularly evaluated using a semiquantitative scale (0-3). RESULTS: Col IV alpha1-chain was demonstrated in GBM of all patients. Three patterns of staining for col IValpha3- and alpha5-chains were observed: positive, negative, and alpha3(IV)-positive/alpha5(IV)-negative. By chi(2)-test, EM class III lesions and complete loss of alpha3(IV)- and alpha5(IV)-antigen were significantly more frequent (P<0.05 and P<0.01) in male patients, but no significant relation was observed between EM classes and immunohistochemical patterns. GBM alterations did not correlate with staining for alpha5(IV)-chain. Intensity of alpha3(IV)-chain staining, however, had a negative correlation (P<0.05) with the severity of GBM basket weaving. CONCLUSIONS: Our results suggest that the alpha3(IV)-chain-containing col IV-network plays a fundamental role in structural and, possibly, functional organization of GBM. Absence of alpha3(IV)-chain in GBM could indicate a more severe renal disease in AS.

Cystinuria type I: identification of eight new mutations in SLC3A1.

BACKGROUND: Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. METHODS: The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). RESULTS: Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. CONCLUSIONS: We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Simultaneous determination of inulin and p-aminohippuric acid in plasma and urine by reversed-phase high-performance liquid chromatography.

A simple, accurate and sensitive high-performance liquid chromatographic method with UV detection was carried out to measure simultaneously plasma and urine concentrations of both p-aminohippuric acid and inulin. Following a simplified acid hydrolysis of the sample, the separation was carried out in 4 min using a C18 reversed-phase column with a flow-rate of 1 ml/min, and monitoring the absorbance at 280 nm. Within the investigated concentration ranges of inulin (0.1-3.2 mg/ml) and p-aminohippuric acid (0.0097-0.3 mg/ml), good linearity (r>0.99) was obtained. Within-run RSD ranged from 2.9 to 6.1% and between-run RSD ranged from 6.4 to 10%. Analytical recoveries were 101-112%, with little differences between plasma and urine samples. The detection limit was 1 microg/ml for all the analytes studied. This method might be ideal for renal function studies where a rapid and reproducible assessment of both renal glomerular filtration rate and blood flow-rate is required.

Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease.

Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with early-onset diabetes and nondiabetic renal disease-particularly renal cystic disease. We investigated a possible role for the HNF-1beta gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1beta gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1beta mutations.

Paecilomyces variotii peritonitis in an infant on automated peritoneal dialysis.

Fungal peritonitis is a serious complication of chronic peritoneal dialysis (CPD) and is frequently associated with CPD drop-out. Paecilomyces variotii, a common saprophytic fungus, rarely causes human infection. To date, only nine adult or adolescent patients with P. variotii peritonitis during continuous ambulatory peritoneal dialysis have been reported. In all patients, successful treatment required antifungal therapy and removal of the peritoneal catheter. We report the first case of P. variotii peritonitis in an infant on automated peritoneal dialysis successfully treated with combined intraperitoneal and oral fluconazole, without removal of the peritoneal catheter.

Hyperparathyroidism during growth hormone treatment: a role for puberty?

We describe three adolescent patients on chronic hemodialysis with a pubertal growth spurt who developed severe hyperparathyroidism during recombinant human growth hormone treatment. Parathyroid hormone levels were raised in parallel with the increase in linear growth in all patients. In two patients, hyperparathyroidism was successfully controlled with an increase in calcitriol dosage. In the third patient, growth hormone had to be withdrawn. We discuss the possibility that puberty is a risk factor for the development of hyperparathyroidism during growth hormone therapy.

Fatal disseminated Nocardia farcinica infection in a renal transplant recipient.

Six years after a renal cadaver transplant, a 20-year-old girl developed multiple painful cutaneous abscesses and bilateral pneumonia secondary to Nocardia farcinica infection. Despite broad in vitro sensitivity to several antibiotic agents and aggressive medical treatment, the patient failed to respond and died after 10 weeks of therapy. We conclude that Nocardia farcinica is a very aggressive organism in immunocompromised patients and is often resistant to antimicrobial agents.

Ambulatory blood pressure monitoring in children with aortic coarctation and kidney transplantation.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) has been found to be of significant importance in clinical practice because numerous blood pressure (BP) measurements may be made throughout the 24-hour period. OBJECTIVE: To assess the clinical utility of ABPM in children with secondary hypertension. METHODS: We studied 37 patients (21 boys and 16 girls), with a mean age of 16.4 +/- 4.1 years, after kidney transplantation and 38 patients (27 boys and 11 girls), with a mean age of 10.2 +/- 2.1 years, after surgical correction of aortic coarctation. Data, expressed as mean +/- SD, were analyzed after dividing the patients into 4 groups. Group A consisted of 25 patients receiving antihypertensive therapy; group B included 12 patients not receiving antihypertensive therapy. Group C included 25 patients operated on before 3 years of age (8 +/- 7 months of age); group D included 13 patients operated on after 3 years of age (74 +/- 29 months of age). RESULTS: In groups A and B, casual BP measurement showed that 16 of 37 patients (43%) were hypertensive; 24-hour ABPM detected a larger number of patients who were hypertensive (23 of 37, 62%); there were 18 in group A and 5 in group B. In groups C and D, casual BP measurement identified 6 of 38 (15%) patients as hypertensive, whereas 24-hour ABPM again identified a higher number (13 of 38, 34%). CONCLUSIONS: Our findings confirm that 24-hour ABPM is more sensitive than casual BP in detecting abnormal BP in patients at high risk for secondary hypertension.