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We performed a case-control study in children diagnosed by the first episode of upper urinary tract infection with or without vesicoureteral reflux to evaluate the association of functional polymorphism of interleukin-8 (-251AT and +2767AG), and its receptor CXCR1 (+2607GC).Genomic DNA was obtained from 265 children with a clinical and laboratory diagnosis of urinary tract infection who were recruited in northeast Italy. The children were subdivided as 173 who were dimercapto-succinic acid scan positive with positive static renal scintigraphy in acute conditions, consistent with the diagnosis of acute pyelonephritis, and 92 who were dimercapto-succinic acid scan negative. Genetic analysis for the same polymorphisms was also extended to a control population of 106 umbilical cord DNA samples.Statistical analysis of genotype data showed that 1) the tested populations were in Hardy-Weinberg equilibrium, 2) there were significant differences between the dimercapto-succinic acid scan positive and negative groups (p=0.049), and the dimercapto-succinic acid scan positive group vs controls (p=0.032) in terms of interleukin-8 -251AT polymorphism frequency, 3) there was also a significant difference in the distribution of IL-8 -251AT and +2767AG polymorphisms between dimercapto-succinic acid scan positive and negative children in the subgroup without vesicoureteral reflux (p=0.03 and 0.02, respectively) and 4) no significant differences were found in the frequency of the distribution of CXCR1 +2607GC polymorphism in all groups.These data suggest that the gene for the proinflammatory chemokine interleukin-8 is involved in susceptibility to acute pyelonephritis during upper urinary tract infection in children with or without vesicoureteral reflux.

Summary Only few data are available on skin disorders in pediatric organ transplant recipients. In order to describe the whole range of dermatological diseases in a population of pediatric organ transplant recipients, we studied a group of 217 consecutive organ transplant recipients (168 kidney, 29 heart, 19 liver, one lung) aged

We report a new high-performance liquid chromatography method developed for measuring inulin in plasma and urine using ion moderated partition chromatography and evaporative light-scattering detection. Samples are deproteinized with a zinc acetate and phosphotungstic acid solution and added with melezitose as an internal standard. The chromatographic separation is carried out in 16 min at a flow-rate of 0.6 ml/min using deionized water as the mobile phase. Within-run precision, measured at four different concentrations (0.050 mg/ml, 0.150 mg/ml, 0.300 mg/ml and 1.200 mg/ml), ranges from 1.7 to 3.4% in plasma and from 1.5 to 3.5% in urine. Similarly, between-run precision is in plasma from 2.0 to 4.3% and in urine from 2.0 to 4.4%. Analytical recovery ranges from 97.9 to 100.1% in plasma and from 99.1 to 99.7% in urine, respectively. Detection limit (signal-to-noise ratio=3) is 5 microg/ml both in plasma and urine. The method is simple, sensitive, without interference due to hexoses or drugs commonly taken by patients with renal diseases, and offers the advantage of measuring inulin without previous hydrolysis of the molecule.

Human parvovirus B19 is considered an etiologic agent of aplastic anemia in immunosuppressed patients. Microscopic vasculitis, with or without renal involvement, has recently been attributed to this viral infection in immunocompetent patients. This study describes four cases of thrombotic renal graft microangiopathy presumably secondary to B19 infection. Twelve to 50 days after transplantation, four patients presented a renal graft dysfunction with creatinine rising to 360 to 1088 micromol/L and requiring hemodialysis in three cases. Renal involvement appeared after a systemic illness characterized by fever, fatigue and arthralgia, aplastic anemia (hemoglobin ranged from 5.3 to 7.8 g/dl), and thrombocytopenia. A thrombotic microangiopathy was observed in the renal biopsies, and the parvovirus B19 genome was isolated by PCR from the specimens. All four patients also became IgM-positive for parvovirus. Three of the four renal biopsies taken at the time of transplantation (T0) from the same patients were found positive for the B19 genome. Graft function recovered, with resolution of the aplastic anemia, within 22 to 110 d. Twenty biopsies performed as routine controls or for suspected acute rejection and nine T0 biopsies of patients with no signs of B19 infection were used. The B19 genome was found in two of 20 posttransplant biopsies and in one of nine T0 biopsies. The temporal association between aplastic anemia and the onset of thrombotic graft microangiopathy, isolation of the viral genome in renal specimens, seroconversion, and endothelial tropism of the virus suggests that B19 could be the etiologic agent of thrombotic microangiopathy in these cases. The development of the disease after infection could depend on other detrimental cofactors, which make the patient more susceptible to microthrombi formation in the renal microvasculature. The renal graft could represent the route of B19 transmission.

Human cystatin C is a basic low molecular mass protein (13,359 Dalton) freely filtered through the glomerulus and almost completely re-absorbed and catabolized by proximal tubular cells. We measured serum cystatin C in 38 kidney transplant patients (23 males, 15 females) aged between 6 and 32 years. To assess renal function, serum and urinary creatinine were also determined in all patients, and creatinine clearance was finally calculated. Cystatin C was determined by a particle-enhanced turbidimetric assay, and creatinine was measured by gas chromatography-mass spectrometry. To compare the diagnostic efficiency of cystatin C with that of creatinine, inulin clearance was performed on 12 renal transplant patients, and receiver operating characteristic (ROC) analysis was applied. The results of this study demonstrate that serum cystatin C significantly increases in renal transplant patients with reduced creatinine clearance (70 mL/min per 1.73 m2) and that the diagnostic accuracy of serum cystatin C is better than of serum creatinine. Cystatin C may be utilized as a very marker of reduced GFR.

Renal calcification is a known complication of long-term furosemide therapy in infants with bronchopulmonary dysplasia (BPD). In a prospective study the clinical course and long-term renal sequelae of renal calcifications of 19 consecutive premature neonates (birthweight < 1250 g) with bronchopulmonary dysplasia who did not receive furosemide were examined. Infants were divided into two different groups on the basis of ultrasound evidence of renal calcifications (RC group) or absence of renal calcifications (NRC group). Serial examinations, performed at the age of 1, 2, 3, 6, 9 and 12 months, showed that 12 infants at the mean age of 68.5 +/- 12.8 days of life had renal calcifications (63%), and 3 of them had nephrolithiasis; 8 had bilateral renal calcifications. Among the 9 survivors, 2 had chronic renal calcifications at the age of 9 months; however, all normalized at the age of 12 months. Twelve infants received hydrochlorothiazide and spironolactone (63%), 17 had prolonged courses of xanthines and dexamethasone (89.5%), while furosemide was not part of the routine pharmacological administration. Statistical analysis showed that birthweight, gestational age, Apgar score and length of parenteral nutrition were comparable in the RC and NRC group infants. Mean serum creatinine, creatinine clearance, fractional sodium excretion and urinary calcium excretion values during the 12-month study period were comparable in the RC and NRC groups. Mechanical ventilation and hospital stay length were instead associated with renal calcification occurrence. The strongest indicator of renal calcification risk for this high-risk population is the severity of the unresolved acute lung disease, where different facets of respiratory management, other than the addition of furosemide, represent sufficient stimuli and renal injury to potentiate stone formation.

Coenzyme Q10 (CoQ10) deficiency has been associated with various clinical phenotypes, including an infantile multisystem disorder. The authors report a 33-month-old boy who presented with corticosteroid-resistant nephrotic syndrome in whom progressive encephalomyopathy later developed. CoQ10 was decreased both in muscle and in fibroblasts. Oral CoQ10 improved the neurologic picture but not the renal dysfunction.

SUMMARYFrom March to October 1993. 15 cases of haemolytic-uraemic syndrome (HUS) in children were detected in a large area of northern Italy, where only 8 cases had occurred in the previous 5 years. Analysis of stool and serum specimens obtained from 14 cases showed evidence of Verotoxin-producingEscherichia coli(VTEC) infection in 13. Serum antibodies to theE. coliO157 lipopolysaccharide (LPS) were found in 8 patients and to the O111 LPS in 2. An O86 VTEC was isolated from another patient. Fourteen children needed dialysis, and 1 died. No obvious epidemiologic link was observed among cases, most of whom lived in small townships. A case-control study did not show an association between HUS and food or exposure to cattle, but suggested an association with contact with chicken coops (OR = 6·5. 95% C.I. 1·2–34·9). However, VTEC were not isolated from stool samples obtained from the chicken coops involved. The risk factors for VTEC infection related to living in rural settlements, including the exposure to live poultry, should be considered in outbreak investigations.

This longitudinal study assessed the influence of post-transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2-19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300-400 mg/m(2) body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post-transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0-12 and AUC0-4 pharmacokinetic profile changed significantly during the first post-transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.

The anthropometry-bioimpedance analysis-nutrition (ABN) score is a recently proposed objective method of assessing malnutrition in children on chronic peritoneal dialysis (CPD) that uses nine parameters based on anthropometry, skinfold thickness and bioimpedance analysis. The aim of this prospective, cross-sectional study was to apply it to children treated with CPD in seven Italian paediatric nephrology centres, with a score of < 10.33 (the 3rd percentile in a population of 264 healthy children) classifying the children as malnourished. The other considered parameters were age, age at the start of dialysis and duration of dialysis; serum haemoglobin, urea, creatinine, total protein, albumin, transferrin, bicarbonate and C-reactive protein; residual urine output; urinary and peritoneal creatinine clearance; and daily protein and energy intake. The study enrolled 43 patients (mean age 10.2 +/- 4.2 years), 21 of whom (48.8%) had an ABN score of < 10.33: 15 with mild, five with moderate, and one with severe malnutrition. The malnourished patients started CPD at a younger age (P < 0.05) and had a longer duration of dialysis (P < 0.01), and a significant worsening in nutritional status was observed in those treated for more than 12 months of dialysis; they also had significantly lower serum albumin, creatinine and haemoglobin levels. In conclusion, protein-calorie malnutrition is common in children receiving CPD. A younger age at the start of dialysis and a longer duration of treatment are clear risk factors, and counterbalance the long-term viability of CPD in paediatric age.

Background. We report on a single-institutional experience with renal transplantation in patients with severe lower urinary tract dysfunction (LUTD) who underwent bladder augmentation or urinary diversion, and assess the long-term results. Methods. From September 1987 to January 2005, 255 patients (161 male and 94 female), 7 months to 39 years old of age (median age at time of transplantation 14 years), received 271 kidney transplants. Etiology of end-stage renal disease was LUTD in 83 cases. Among these patients, 24 had undergone bladder augmentation or urinary diversion. Results. We identified two groups of patients surgically treated due to LUTD: group 1 included 16 patients (eight male, eight female) aged 4 to 39 years (median 19 years) with bladder augmentation, whereas in group 2, seven patients (five male, two female) 7 months to 31 years old (median 17 years) with incontinent urinary diversion were reported. In the first group, surgical complications after kidney transplantation included one urinary fistula, one ureteral stenosis. Three patients of second group developed recurrent urinary tract infection. Cumulative graft survival rates of all patients transplanted was 69.4% after 15 years, whereas in the two investigated groups, group 1 and group 2, was 80.7% and 55.5% respectively (P=NS.). Conclusions. Drainage of transplanted kidneys into an augmented bladder or urinary diversion is an appropriate management strategy when the native bladder is unsuitable. Kidney transplantation in patients with bladder augmentation or urinary diversion for LUTD let achieve similar results to those obtained in the general population with normal lower urinary tracts.

Background. The management of cyclosporine therapy in pediatric kidney-transplant recipients is largely based on single center's experience rather than on a univocal pharmacokinetic approach based on therapeutic drug monitoring. A prospective multicenter trial was designed to address the question whether C2 blood level monitoring of cyclosporine microemulsion therapy is feasible in the pediatric setting. Methods. Sixty-four pediatric kidney-transplant recipients receiving a triple immunosuppressive regimen based on cyclosporine microemulsion had their cyclosporine dose adjusted to the same protocol-defined C2 targets from the time of the transplant until 2 years posttransplant. The interim analyses after 1 year of enrolment is presented in this study. Results. One-year patient and graft survival were 100% and 94.8%, respectively. One-year rejection rate was 15%. C2 management of cyclosporine did not affect graft function: 1-year serum creatinine and glomerular filtration rate were 1.3±1 mg/mL and 71.2±20 mL/min/1.73 m 2 , respectively. C2 was the best single-point predictor of the area under the concentration curve throughout the entire follow-up, with a mean coefficient of correlation of 0.97±0.01. Conclusions. C2 management of cyclosporine microemulsion therapy is effective and safe in pediatric kidney-transplant recipients given a combined immunosuppressive treatment.

The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2-20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children

This study was undertaken to determine the role of aquaporin 2 (AQP2) in the impaired urinary concentrating capacity observed in patients who underwent pyeloplasty because of congenital unilateral hydronephrosis as a result of pyeloureteral junction disease. Twelve children (mean age, 8 +/- 2 mo) were examined in the study. From day 1 to day 5 after surgery, the urine was collected separately from pyelostomy draining only from the postobstructed kidney and from the bladder catheter draining mostly from the contralateral kidney used as internal control. After pyeloplasty, the postobstructed kidney was characterized by a reduced urinary excretion of AQP2 (approximately 54%) associated with polyuria that persisted from day 1 to day 5 (433 +/- 58 versus 310 +/- 74 ml/24 h at day 1; 326 +/- 44 versus 227 +/- 26 ml/24 h at day 5). In parallel, urine osmolality from the postobstructed kidney was significantly reduced compared with the contralateral kidney (111 +/- 12 versus 206 +/- 49 at day 1; 136 +/- 24 versus 235 +/- 65 mOsm/kg at day 5). Creatinine clearance from the postobstructed kidney was not significantly different compared with the contralateral kidney throughout the 4 d after surgery. However, on day 5, creatinine clearance from the postobstructed kidney became significantly lower. Prostaglandin E2 in the urine from postobstructed kidneys was found to be twofold higher than in the contralateral samples (26.0 +/- 6.7 versus 13.5 +/- 2.5 at day 5). It is concluded that (1) the selective downregulation of AQP2 in postobstructed kidney may account for the higher excretion of hypotonic urine, and (2) the local increase in prostaglandin E2 synthesis in postobstructed kidney may be involved in AQP2 downregulation and in maintaining a GFR similar to that of the contralateral kidney.

We assess the effect of the prune-belly syndrome (PBS) on renal transplantation outcome. Six renal transplantations were performed in five boys affected by PBS (median age 5.8+/-2.1 years, median weight 13.6+/-2.4kg). Renal graft survival, graft function, lower urinary tract dysfunction, urinary tract infections (UTIs), associated complications and patients' survival after 1 and 5 years of follow-up were analysed. The rate for 1-5-year graft survival was 66.7% (mean serum creatinine 98-103 micromol/l). The surgical treatment of the documented bladder obstruction (two patients) and the severe abdominal wall deficit (one patient) led to a reduction of UTI: the patients maintained their native urinary tract and none received prophylactic antibiotics. The lack of abdominal wall musculature led to severe mechanical complication in one patient, but Monfort's abdominal wall reconstruction was able to restore the graft's function. The outcome of patients with PBS who undergo renal transplantation is good. Before the transplant, an accurate assessment of urinary tract anomalies and deficiency of the abdominal wall musculature is mandatory, to program the appropriate treatment and obtain a good long-term prognosis for the renal graft.

Plasma homocysteine, a new cardiovascular risk factor in both children and adults, is higher in chronic renal failure or kidney transplant patients. This alteration has been linked, in chronic renal failure, to plasma protein damage, represented by increased L-isoaspartyl residues. We measured plasma homocysteine levels and plasma protein damage in pediatric patients from four different Italian regions with conservatively treated renal failure; hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), or transplants, to establish the presence of protein damage and the relative role of hyperhomocysteinemia.High performance liquid chromatography (HPLC) separation measured total plasma homocysteine levels, using precolumn derivatization with ammonium 7-fluorobenzo-2-oxa-1, 3-diazole-4-sulphonate (SBD-F). Plasma protein L-isoaspartyl residues were quantitated using human recombinant protein carboxyl methyl transferase (PCMT).In all patient groups, homocysteine levels were significantly higher with respect to the control (Control: 6.87 +/- 0.73 microM) conservatively treated, 14.19 +/- 1.73 microM; hemodialysis, 27.03 +/- 4.32 microM; CAPD, 22.38 +/- 3.73 microM; transplanted, 20.22 +/- 2.27 microM, p0.001 vs. control]. Plasma protein damage was significantly higher in conservatively treated, hemodialysis (HD) and CAPD patients, while in transplant patients it was no different from the control.We concluded that in pediatric patients of different Italian geographical origin, plasma homocysteine levels were significantly higher in all groups with respect to healthy children; therefore contributing to the elevated cardiovascular risk present in these patients. Plasma protein L-isoaspartyl content was higher in renal failure patients, but kidney transplant patients had normal levels, indicating that this kind of protein damage relates more to the toxic action of uremic retention solutes, than to plasma homocysteine levels.

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.

This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft-versus-host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8.6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5-year overall survival was 69% for responding patients vs 12% for non-responders (P = 0.001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5-year overall survival was 96% for responders vs 58% for non-responders (P = 0.04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

In this study we compared patient and technique survival of 163 new hemodialysis (HD) patients (age 11.4+/-3.1 years) and 295 peritoneal dialysis patients (7.7+/-4.8 years. P0.001), treated in 23 dialysis centers participating in the Italian Registry of Pediatric Chronic Peritoneal Dialysis (CPD) during the years 1989-2000. Three HD (1.8%) and 17 CPD (5.8%) patients died; the overall average death rate was 9.8/1,000 patient-years in HD and 29.8/1,000 patient-years in CPD patients. No statistically significant difference in patient survival between CPD and HD was found, while the survival of 102 CPD children younger than 5 years at the start of dialysis was lower ( P=0.0001) than that of 193 CPD and 160 HD patients aged 5-15 years. We registered 12 modality failures among HD (7.4%) patients and 44 among CPD (14.9%) patients. The main causes were vascular access failure and patient choice in HD, and infection in CPD patients. Technique survival was lower ( P=0.007) in CPD than in HD patients; a statistically significant difference ( P=0.01) was also observed between both the 0- to 5- and the 5- to 15-year-old CPD patients and the HD patients aged 5-15 years. Logistic regression analysis confirmed age at initiation of dialysis to be a predictor of patient death ( P=0.0001) in the whole patient population, and of technique failure in HD ( P=0.006) but not in CPD patients ( P=0.16).

PAX2, a homeotic gene of ‘paired box family’, is a nuclear transcription factor expressed in mesenchymal/epithelial conversion during the early stages of nephrogenesis; however, its repression is necessary for terminal differentiation of mature tubular cells. Transgenic overexpression in animal model causes epithelial hyperproliferation and microcyst formation. In humans, PAX2 expression has been observed in cystic and dysplasic tubular epithelia in kidney malformation and in kidney disease. We have investigated PAX2 expression and its colocalization with cytokeratin and/or vimentin in 17 biopsies of juvenile nephronophthisis (NPH), an autosomal-recessive renal disease characterized by diffuse renal fibrosis and occasional cysts. Fourteen cases were analyzed for deletion and mutation in the NPH1 gene locus and 33% resulted to be deleted or mutated; for the remaining cases the diagnosis was based on clinical and pathological criteria. The control group included 4 congenital dysplastic kidneys, and 10 biopsies of nephropathies with secondary chronic tubulointerstitial damage. In all cases of renal dysplasia a strong nuclear positivity was observed in immature tubules surrounded by αSMA-positive mesenchymal cells. In NI biopsies the tubular epithelia were almost PAX2 negative, although tubulointerstitial damage was severe. In 14/17 NPH1 moderate-to-strong nuclear PAX2 positivity of tubular cells was observed, particularly in cystic distal tubules located at the corticomedullary junction, but also in proximal tubular sections. The PAX2 signal co-localized more with cytokeratin staining than with vimentin. Our results confirm the observation of PAX2 expression in immature dysplastic tubules and its repression in mature renal tubular cells, also in the presence of severe secondary interstitial fibrosis. PAX2 seems to be overexpressed in NPH. The genetic defect of NPH, a disease probably due to a primary defect along the cascade of mesenchymal epithelial differentiation, could generate a functionally abnormal protein involved in focal adhesion signaling and cell/matrix interaction. The failure of PAX2 repression or its reactivation in NPH could be a marker of hyperproliferation and incomplete maturation of epithelial tubular cells, probably due to a defect cell/matrix cross-talk, and involved in interstitial fibrosis and cysts formation.

To evaluate the efficacy of renal transplantation in small pediatric patients, we have reviewed 41 allografts performed in 39 children (28 M/11 F) less than 6 years of age between 1987 and 1998 in the North Italy Transplant Program. Of these patients, 39 had a cadaver donor and 2 a living-related donor, with ages ranging from 20 days to 35 years. The mean follow-up was 56 months. Graft survival was 74.5% and 70.5% at 1 and 5 years, respectively. The causes of graft lost were acute rejection (4), graft vascular thrombosis (4), and hemolytic uremic syndrome recurrence (1). Only 1 patient has died due to chickenpox. Double and triple immunosuppressive therapies were used in 63% and 37% of patients, respectively, on the basis of different center protocols, without differences in graft survival. Steroids were successfully administered on alternate days in 37% of patients, 6-12 months after transplantation. Thrombosis was reported in 2 of 6 kidneys from donors less than 1 year of age and in 2 of 35 donors older than 1 year (P0.05). Thirty rejections occurred in 23 patients: 7 episodes were steroid resistant and were treated with ATG/OKT3. Thirty-four infections were reported in 16 of 41 patients; of these 17 were viral, 14 bacterial, and 3 due to Mycoplasma. Four surgical complications were reported: 1 graft artery stenosis, 1 ureteral stenosis, 1 urinary leak, and 1 lymphocele. Mean height standard deviation score improved from -2.0 +/- 1.3 pre transplantation to -1.8 +/- 1.4, -1.5 +/- 1.3, and -1.5 +/- 1.5 at 1, 2, and 5 years post transplantation. Linear growth was significantly better in infants treated with alternate-day steroids. Hypertension was a frequent complication, since 19 of the 30 patients with a 5-year follow-up were still being treated with antihypertensive drugs. In conclusion, graft survival in patients less than 6 years old is satisfactory and similar to that obtained in children aged from 6 to 18 years (70.5% vs. 78.9% at 5 years, P = NS). Consequently, since there are many difficulties in managing infants on maintenance dialysis, an early transplant should be considered. Donors older than 24 months carry a low risk of vascular thrombosis and may be successfully grafted in infants.

A growing body of evidence identifies the renin-angiotensin system as a key factor in the onset and progression of renal damage in chronic partial obstruction, which often represents a complex diagnostic challenge. A prospective study was undertaken to evaluate the role of captopril mercaptoacetyltriglycine-3 (MAG-3) renography as an early diagnostic test of obstruction. We report the results in a subgroup of children who underwent surgical correction for pyeloureteral obstruction.Pyeloplasty was performed in 12 patients, including 10 males, 2 to 72 months old (median age 7) with unilateral hydronephrosis, including normal renal function and blood pressure. Basal and captopril enhanced diuretic renography with 99mtechnetium MAG-3 was performed within 24 hours using the same hydration and diuretic stimulus (0.75 mg./kg. furosemide), and 0.75 mg./kg. captopril was administered orally 60 to 90 minutes before scintigraphy.No adverse effects or modifications of the blood pressure were observed after captopril administration. The diuretic response was deeply worsened by angiotensin converting enzyme inhibition in each hydronephrotic kidney even when the basal study was only slightly abnormal (15-minute washout basal -27 +/- 16%, after captopril -9 +/- 13, p0.005). After surgical correction the diuretic washout during angiotensin inhibition appeared normal in all patients (15-minute washout -56 +/- 14%). Separate renal function and parenchymal transit of MAG-3 were not modified by angiotensin converting enzyme inhibition, preoperatively or postoperatively.Our data confirm the influence of angiotensin on the kidney excretory system in human hydronephrosis and suggest a role for captopril enhanced diuretic renography in the early diagnosis of pyeloureteral obstruction. Further work is needed to evaluate angiotensin converting enzyme inhibition as a protective agent in obstructive nephropathy.

The purpose of this study was to determine the frequency and the outcome of de novo malignancies in a cohort of renal transplant paediatric patients. The records of 493 kidney transplants, carried out in 454 paediatric recipients at the three paediatric transplant centres of the North Italy Transplant programme (NITp, Italy) were reviewed. 10 cases of malignancies (2.2%) comprising both PTLD (post-transplant lymphoproliferative disorders) (6 cases, 1.3%) and non-PTLD malignancies (4 cases, 0.88%) were reported. Non-PTLD included one urothelial carcinoma and one Wilms' tumour of the recipient's left native kidney, one abdominal dysgerminoma and one optic nerve glioma of the left eye. The PTLD consisted of localised or disseminated Epstein–Barr virus (EBV)—associated B-lymphocyte monoclonal (5 cases) and polyclonal (1 case) proliferations. All patients suffering from PTLD had been EBV-negative at the time of transplantion, but developed EBV primary infection after transplantion. All PTLD patient donors were EBV-positive. In addition, all but 1 patient received, before and/or after transplantation, a range of immunosuppressive drugs in addition to the baseline prophylactic immunosuppressive regimen. Moreover, 3 patients suffered from syndromes associated with a genetic predisposition to cancer. Finally, the malignancies reported here were associated with 20% graft failure and 20% mortality rates.

A nonradioactive in situ hybridization technique was utilized for the rapid and early diagnosis of cytomegalovirus (CMV) infection in children undergoing kidney transplantation. The cellular samples were obtained directly from the organs thought to be affected on the basis of clinical findings: bronchoalveolar lavage during interstitial pneumonia (7 samples from 6 cases); fine-needle aspiration biopsy (FNAB) of the liver during acute hepatitis (1 case); kidney FNAB and peripheral blood where there was a greater than or equal to 25% creatinine rise with or without fever (26 episodes). Standard virus isolation procedures and an immunofluorescent technique on short-term cultures of human fibroblast cells were performed as a control. 6/23 children followed had a symptomatic CMV infection (4 had interstitial pneumonia; 1 had acute hepatitis, and there was 1 case of creatinine rise with fever). In all cases, the diagnosis was provided by in situ hybridization in less than 24 h. These results were confirmed 48 h later by immunofluorescence and after 5-25 days by standard viral cultures. In situ hybridization with a biotinylated probe proved to be a rapid and sensitive method for diagnosis of CMV disease, when performed on specimens obtained from the involved organs at an early stage of the infection. This diagnostic approach allowed a specific antiviral therapy to be undertaken promptly.

Neurophysiological studies have shown defects in peripheral conduction in up to 75% of adults with end-stage renal disease (ESRD), though abnormalities of central conduction seem more variable. There are no comparable pediatric data. We therefore measured median nerve somatosensory evoked potentials (SEPs) in 10 children with ESRD, maintained by hemodialysis, who had no neurological signs or symptoms, and compared the results with those for age-matched controls. The latencies of N9, P14, N20 and P22, and interpeak latencies, N9-N20, N9-P14 and P14-N20, were not significantly different between the two groups (Student's t test). However, the children with ESRD were significantly retarded in growth and when arm length was taken into account, a significant difference in peripheral conduction was revealed. There was no correlation with other indexes of disease severity (parathormone, aluminium, Hb, Na, K, Cl, BUN and creatinine). SEPs appear to reflect subclinical changes in peripheral conduction in sensory pathways in children with ESRD which are not correlated with other measures of disease severity.

The aim of this study was to evaluate the effect of correction of chronic anaemia on the physical performance and the cardiovascular response to effort in children with end-stage renal disease (ESRD) maintained by haemodialysis. Seven patients (mean age 13.9 years) underwent triangular-type treadmill exercise testing before [haemoglobin (Hb) 6.3 +/- 0.9 g/dl] and after (Hb 11.2 +/- 1.2 g/dl) anaemia correction with recombinant human erythropoietin (rHuEPO). After treatment, the work-load reached, the peak oxygen uptake and average ventilatory anaerobic threshold (VAT) values were significantly increased (P less than 0.01, P less than 0.001, P less than 0.05 respectively). VAT values, expressed as a percentage of normal values, increased from 55.7 +/- 16.6% to 82.4 +/- 21%. This improvement correlated well with the increase in Hb (r = 0.79). Oxygen pulse also increased significantly, when tested after anaemia correction. In conclusion, these data demonstrate that when the anaemia of children with ESRD is corrected with rHuEPO, there is a clear improvement in aerobic work capacity and effort tolerance.

We investigated glomerular filtration rate and renal function reserve after the surgical relief of partial obstruction.We evaluated 4 boys and 1 girl 9 to 14 years old who underwent pyeloplasty because of unilateral ureteropelvic junction obstruction. Contralateral normal kidneys served as controls. The glomerular filtration rate (inulin clearance), and urinary excretion of prostaglandin E2, thromboxane B2 and endothelin were determined at baseline and after a meal of 4 gm./kg. cooked unsalted red meat on day 4 postoperatively. Tests were repeated the following day 1 hour after the oral administration of 20 mg./kg. aspirin, an inhibitor of prostaglandin E2 synthesis. Urine was collected separately through a bladder catheter and another catheter placed in the upper renal pelvis at surgery.Glomerular filtration rate at baseline was significantly greater in normal than in surgically treated kidneys (77.2 ml. per minute, range 60 to 98 versus 63.6, range 43 to 78, p = 0.04). Aspirin did not change baseline inulin clearance in normal kidneys but it significantly decreased the glomerular filtration rate in operated renal units (-4% versus -26.4%, p = 0.04). The concentration of all vasoactive compounds was not significantly different in the urine specimens of normal and operated kidneys. The administration of aspirin resulted in a significant decrease in mean urinary prostaglandin E2 excretion plus or minus standard error in operated but not in normal renal units (0.64+/-0.12 ng. per minute versus 0.27+/-0.06, p = 0.04). When expressed as mean versus baseline values, protein induced glomerular hyperfiltration seemed lower in operated than in contralateral intact kidneys (6.9% and 12.4%, respectively).In the immediate postoperative period previously obstructed kidneys maintain renal function via mechanisms that depend on the activation of prostaglandin, mimicking normal renal function. This effect is decreased by drugs that inhibit prostaglandin E2 production. Therefore, renal damage may be present when the glomerular filtration rate appears normal.

We report the clinical and morphological features of an unusual hepatorenal disorder in 2 patients. The main clinical features were early onset of cholestatic liver disease and progressive tubulointerstitial nephritis, leading to renal death in early childhood. Renal histology showed interstitial fibrosis, tubular atrophy and dilatation, glomerular cysts in the cortex and periglomerular fibrosis; liver histology was characterized by portal fibrosis and bile duct abnormalities. Evaluating the 12 patients published in the literature, the long-term prognosis of the liver function appears bad, suggesting the possibility of a combined liver and kidney transplantation.

We characterized the lipid-lipoprotein abnormalities encountered in a series of 45 nonnephrotic uremic children with various degrees of chronic renal insufficiency. A mild hypertriglyceridemia associated with decreased serum high-density lipoprotein cholesterol levels was confirmed. The correlation between high-density lipoprotein cholesterol and creatinine clearance showed a power behavior with a marked decrease in high-density lipoprotein cholesterol below a creatinine clearance value of 40 ml/min/1.73 m2. A number of uremic children accumulate an abnormal population of very low-density lipoprotein particles in their plasma. On agarose gel electrophoresis these particles migrate as a slow moving pre-beta band and are clearly distinguished from the regular fast moving pre-beta very low-density lipoprotein band. This electrophoretic phenomenon has been called double pre-beta lipoproteinemia. The prevalence of double pre-beta lipoproteinemia increased significantly with the degree of impairment of renal function, reaching highest figures in patients on hemodialysis. Accordingly, the very low-density lipoprotein cholesterol/triglyceride ratio also was significantly increased. The double pre-beta lipoproteinemia phenomenon was not detected in any of the control, nonuremic subjects. The clinical importance of double pre-beta lipoproteinemia in uremic plasma is related to its possible atherogenic role.

Urinary excretion of the most widely studied renal stone promoting (calcium, oxalate, uric acid and phosphate) and inhibiting (citrate, magnesium, pyrophosphate and glycosaminoglycans) factors, as well as the Tamm-Horsfall mucoprotein, was evaluated in 14 children with idiopathic calcium nephrolithiasis, 6 children with renal stone disease secondary to excretory malformations and 19 normal controls.No statistically significant differences in urinary excretion of promoting and inhibiting factors were found in children with idiopathic calcium nephrolithiasis but the relationship between promoting and inhibiting factors was changed as shown by an abnormal ratio of oxalate/citrate X glycosaminoglycans. This finding suggests that there is an imbalance between promoting and inhibiting factors in children with idiopathic calcium nephrolithiasis, and it is not detected by assay of each single substance.

We report 2 cases of cystinuria in which a nephrotic syndrome developed during treatment with alpha-mercaptopropionylglycine. This syndrome resolved after withdrawal of the drug and it did not recur when the alpha-mercaptopropionylglycine was given again in lower doses. The hypothesis is made that the nephrotic syndrome was dose-related. The alpha-mercaptopropionylglycine must be used in doses less than 50 mg./kg per day with regular monitoring of 24-hour urinary protein in cystinuric children.

In a retrospective, double-blind study, we analyzed, utilizing an immunohistochemical technique, the distribution of Endothelin (Et) in 20 renal biopsies of 17 children with nephrotic syndrome (NS): 9 cases of steroid-responsive and 8 of steroid-resistant minimal-change disease (MCD) and 3 cases of focal segmental glomerulosclerosis (FSGS). Thirteen out of 20 biopsies (9/9 steroid-responsive MCD and 4/8 steroid-resistant MCD) showed a weak positivity of the vascular endothelial cells, as the normal renal tissue samples obtained from tumor nephrectomies. Seven out of 20 biopsies, all steroid-resistant NS, showed a marked positivity of the vascular endothelium and of the tubules and/or interstitial cells. In 4 of these 7 cases (1 MCD, 3 FSGS) a positivity of glomeruli was also revealed. The positivity of vascular endothelium seems to confirm its central role in Et production. The marked immunoreactivity detected in the endothelial cells and other renal components reveals a local increase in Et in some steroid-resistant MCD and, particularly, in FSGS. These preliminary observations suggest that Et may participate (cause or epiphenomenon) in the mechanisms underlying the development of glomerulosclerosis and the progression of renal damage.

Photopheresis (ECP) is a new type of photochemotherapy, used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8-methoxypsoralen (8-MOP) and ultraviolet light A (UVA) in an extracorporeal system and then reinfused. Skin exposure to 8-MOP and UVA (PUVA) has been shown to relieve cutaneous symptoms of graft-versus-host disease (GVHD) in bone marrow transplant (BMT) recipients. ECP, which is similar in some ways to PUVA, has been used in this study to treat four paediatric patients who developed chronic GVHD following BMT and in whom GVHD had failed to respond to conventional immunosuppressive therapy. Following ECP, skin lesions cleared almost completely and pulmonary function tests improved in two of three patients with cutaneous and lung involvement. Serum bilirubin and transaminases gradually normalized, and gammaGT decreased considerably in the remaining patient who had a severe cholestatic hepatopathy. The Karnofsky performance score increased to 90% in the three patients with positive responses to ECP and remained unchanged (40%) in the patient who did not respond. Immunosuppressive therapy was reduced in three patients and eventually discontinued in two. No significant side-effects were observed during the treatment. Our results suggest that ECP is a non-aggressive treatment that may benefit patients with chronic GVHD who do not respond to standard immunosuppressive therapy.

Photopheresis (ECP) is a new form of photochemotherapy that induces a selective inhibition of the host response to foreign histocompatibility antigens and reverses allograft rejection after organ transplantation. This report describes four adolescent patients with recurrent rejection episodes after renal transplantation, all uncontrolled using standard protocols of immunosuppression (intravenous steroids and OKT3), yet successfully treated with a 6-mo course of ECP. The ECP treatment was performed at weekly intervals during the first month, at 2-wk intervals during the second and third months, and then monthly for another 3 mo. Creatinine clearance improved throughout the treatment in three patients and remained unchanged in one. All patients had a pre-ECP biopsy with a grade 2 or 3 rejection (Banff) with a diffuse infiltrate CD8, CD14, LFA-1 (166 cells positive/0.048 mm2), and VLA-4 (51 cells positive/0.048 mm2) positive, as well as a tubular expression of HLA-DR (6.2 sections of tubule positive/0.048 mm2), ICAM-1, and VCAM-1 (3.1 and 2.9 sections of tubule positive/0.048 mm2). A strong reduction of cell infiltrate and expression of LFA-1 (6.6 cells positive/0.048 mm2). VLA-4 (0.7 cells positive/0.048 mm2), HLA-DR (0.2 section of tubules positive/0.048 mm2), ICAM-1 (0.3 section of tubules positive/0.048 mm2), and a disappearance of VCAM-1 staining were observed in the biopsies performed after 3 mo of ECP. All patients remained rejection-free during ECP, without infections or other complications commonly observed with increasing doses of standard immunosuppression. The clinical improvement allowed a progressive reduction of oral steroids in three of the four patients treated.

The residual enzyme activity in tissues of a 6-year-old boy with myoglobinuria and carnitine palmitoyltransferase (CPT) deficiency was studied with malonyl-CoA, a specific inhibitor of CPT-I in rat tissues. In this patient the enzyme deficiency was limited to the CPT fraction insensitive to malonyl-CoA, since the residual activity was an increased amount of CPT sensitive to the inhibitor. CPT sensitivity to malonyl-CoA was also assayed in human liver mitochondria, and inhibition was similar to that found in rat liver. Moreover, comparative data on human liver mitochondria and biopsy specimens showed that, after freeze-thawing and homogenization, CPT sensitivity to malonyl-CoA was decreased in both these preparations, indicating that studies of CPT inhibition by malonyl-CoA in homogenates of frozen tissues may be equated to those in homogenates of frozen mitochondria.

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen and ultraviolet light. The treatment seems to induce an inhibition of both humoral and cellular rejection after transplantation. Objective Since recurrent rejection (RR) continues to be a severe complication after heart transplantation (HTx) and the immunosuppressive regimes used for the treatment are often associated with increased morbidity and mortality, we investigated whether ECP could have a beneficial effect on the number and severity of rejection episodes. Methods Eleven HTX recipients (5 M and 6 F, mean age 48.5 yrs) with RR were enrolled in the study. ECP was performed at weekly intervals during the 1st month, at 2 week intervals during the 2nd and 3rd month, and then monthly for another 3 months. Results The fraction of biopsies (EMB) with a grade 0/1A rejection increased during ECP from 46% to 72% while the EMB showing a 3A/3B rejection decreased from 42% to 18%. It is also noteworthy that out of the 78 EMB performed during ECP only one showed a 3B rejection in comparison with 13 out of 110 EMB in the pre-ECP period. Six rejection relapses were observed in a total follow-up of 60 months, two of them occurring during the tapering of oral steroid. Four relapses were reversed by ECP, one by IV steroids and the last by methotrexate after the failure of both IV steroids and ECP. The mean doses of immunosuppressive drugs resulted lower after 6 months of ECP: steroids were reduced from 13 to 8.25 mg/day, cyclosporine from 375 to 285 mg/day, azathioprine from 55 to 35 mg/day. Conclusions ECP is a well tolerated treatment. Its administration allows better RR control and significant reduction in immunosuppressive therapy. (Int J Artif Organs 2000; 23: 49–54)

Recurrent rejection is an uncommon, severe complication after heart transplantation that is associated with a poor long-term prognosis. Photopheresis (ECP), a new form of extracorporeal photo-chemotherapy used for the treatment of cutaneous T cell lymphoma and several autoimmune diseases, has also been used for prevention and treatment of acute rejection in heart transplant recipients. It seems to induce specific suppression of both cellular and humoral rejection. In this study, we evaluated whether ECP added to standard therapies allowed better control of rejection and reduction of conventional immunosuppressive drugs in patients with repeated rejection episodes. Eight heart transplant recipients (6 men and 2 women, mean age 48 yr), with recurrent rejection were treated with ECP for 6 months. Endomyocardial biopsies (EMB) were performed monthly. As a result of treatment, 7 patients on ECP experienced a reduction of the number and severity of rejection episodes. The fraction of EMB negative for rejection increased from 13 to 41%, whereas the fraction of specimens with multifocal and/or diffuse moderate lymphocytes infiltration (grades 3A and 3B) decreased from 41 to 21%. ECP allowed reductions of daily immunosuppressive therapy: prednisone by 44% (16.9 vs. 9.4 mg), cyclosporine by 21% (366 vs. 291 mg), and azathioprine by 29% (137 vs. 97 mg). No major side effects were observed. We conclude that, although the number of patients is small, the use of ECP was safe and associated with improved control of recurrent rejection. This allowed tapering of immunosuppressive drugs, which was particularly useful in two patients with insulin-dependent diabetes and one with sternal wound osteomyelitis.

In chronic renal failure high serum urea levels (sUrea) are correlated with the onset of uremic symptoms. Urea has generally been considered relatively non-toxic, functioning more as a surrogate for other toxic solutes; however, it has been recently reported that it can contribute to uremic toxicity. Clinically sUrea are often difficult to interpret because of the wide range of kidney functions. To obtain a practical and easily accessible tool to evaluate sUrea, we have produced percentile curves for different ranges of chronic renal failure, defined with creatinine clearance ( C(Cr)) obtained with the Schwartz formula. Data were obtained from the Italian Pediatric Registry of Chronic Renal Failure (ItalKid); its inclusion criteria are: (1) C(Cr )75 ml/min per 1.73 m(2), (2) age20 years at time of registration, and (3) conservative treatment. To obtain the percentiles, the following patients were excluded: patients with an underlying disease, a concomitant treatment, or a disorder that could affect urea metabolism, per se, and/or food intake, and patients aged2 years. The study group included 690 subjects (mean age 9.56+/-4.54 years, 485 males). In total, 2,085 observations (C(Cr )and sUrea) were available for the construction of the percentile curves. A median of 258 (range 99-380) observations was obtained for each of the eight different categories of C(Cr )(intervals of 10 ml/min per 1.73 m(2)). The 10th, 25th, 50th, 75th, and 90th percentiles were calculated and a graph was produced. Patients with the highest urea percentiles showed significantly higher plasma levels of phosphorus and parathyroid hormone and significantly lower hemoglobin concentrations and bicarbonate levels. Our percentile curves may help to identify subjects with inappropriate sUrea for a given C(Cr).

Anemia, through a hyperkinetic state, is an Important contributor to myocardial function impairment. To determine the cardiovascular effects of recombinant human erythropoietin (rHuEPO) therapy, 10 chronic peritoneal dialysis (CPD)-treated anemic children were studied be fore and during 18 months of treatment. The following parameters were recorded: hemoglobin (Hb) [percent of target level (TL) = x 2 standard deviations of normal Hb values for age and sex], heart rate (HR, beats/minute), mean arterial pressure (MAP, mmHg), end-diastolic left ventricular diameter (EDLVD, mm/sm BSA), shortening fraction (SF, percent), and Interventricular septal thickness (IVS, mm/sm BSA). Student's t-test for paired data showed (vs time before treatment, TO) a progressive Increase In Hb, a progressive decrease In HR, and a progressive Increase In MAP. EDLVD progressively decreased, while SF and IVS remalned unchanged throughout the study. Regression analysis showed a close correlation between anemIa cor rection and decrease of HR (p Our data indicate that anemia correction In these patients Is mainly associated with a decrease in hyperkinetic state (HR reduction with SF unvaried), while left ventricular function and dimensions remain normal, despite an Increase in MAP.

Patient hospitalization was compared in 207 pediatric patients (age ≤15 years at the start of dialysis) on chronic peritoneal dialysis (CPD) (127 patients) or center hemodialysis (HD) (80 patients), treated in 17 dialysis centers during the period 1989 to 1994, and followed up for at least three months. The hospitalization rate was expressed as hospital days per patient-month, and was calculated on the overall period of treatment and separately for the first and second year. Since the age at start of dialysis markedly differed between CPD (8.2±4.7 years) and HD (11.2±2.9 years) patients (with no HD patient younger than five years), results are separately presented in three patient groups: CPD patients aged A statistically significant difference in total days hospitalized was found between each of the two groups of CPD patients and the HD patients; the results for hospitalization for dialysis-related complications were higher in the group of younger children on CPD, while the difference between the two age-matched groups of patients on CPD and HD was not significant.