Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

The use of cinacalcet after pediatric renal transplantation: an international CERTAIN Registry analysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce. METHODS: In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile). RESULTS: At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m2, plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported. CONCLUSIONS: This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed.

Steroid withdrawal improves blood pressure control and nocturnal dipping in pediatric renal transplant recipients: analysis of a prospective, randomized, controlled trial.

BACKGROUND: Variable effects of steroid minimization strategies on blood pressure in pediatric renal transplant recipients have been reported, but data on the effect of steroid withdrawal on ambulatory blood pressure and circadian blood pressure rhythm have not been published so far. METHODS: In a prospective, randomized, multicenter study on steroid withdrawal in pediatric renal transplant recipients (n = 42) on cyclosporine, mycophenolate mofetil, and methylprednisolone, we performed a substudy in 28 patients, aged 11.2 ± 3.8 years, for whom ambulatory blood pressure monitoring (ABPM) data were available. RESULTS: In the steroid-withdrawal group, the percentage of patients with arterial hypertension, defined as systolic and/or diastolic blood pressure values recorded by ABPM > 1.64 SDS and/or antihypertensive medication, at month 15 was significantly lower (35.7%, p = 0.002) than in controls (92.9%). The need of antihypertensive medication dropped significantly by 61.2% (p < 0.000 vs. control), while in controls, it even rose by 69.3%. One year after steroid withdrawal, no patient exhibited hypertensive blood pressure values above the 95th percentile, compared to 35.7% at baseline (p = 0.014) and to 14.3% of control (p = 0.142). The beneficial impact of steroid withdrawal was especially pronounced for nocturnal blood pressure, leading to a recovered circadian rhythm in 71.4% of patients vs. 14.3% at baseline (p = 0.002), while the percentage of controls with an abnormal circadian rhythm (35.7%) did not change. CONCLUSIONS: Steroid withdrawal in pediatric renal transplant recipients with well-preserved allograft function is associated with less arterial hypertension recorded by ABPM and recovery of circadian blood pressure rhythm by restoration of nocturnal blood pressure dipping.

Static and Functional MR Urography to Assess Congenital Anomalies of the Kidney and Urinary Tract in Infants and Children: Comparison With MAG3 Renal Scintigraphy and Sonography.

OBJECTIVE: The purpose of this study is to compare functional MR urography (MRU) with the results of ultrasound and radionuclide 99mTc-mercaptoacetyltriglycine (MAG3) scintigraphy in evaluating morphologic findings, split renal function, and urinary tract obstruction in pediatric patients. MATERIALS AND METHODS: Pediatric patients with proven congenital anomalies of the kidney and urinary tract were included (n = 112). The morphologic findings of MRU were compared with previous diagnostic ultrasound findings. For evaluation of split renal function and urinary tract obstruction, MAG3 scintigraphy was used as a reference standard. RESULTS: MRU provided detailed morphologic information of the whole urinary tract for all 112 patients. In 94.6% of cases (n = 106), diagnostic findings could be verified, and in 5.4% of cases (n = 6), more detailed information could be gained. Equivalent split renal function showed good concordance between functional MRU and MAG3 scintigraphy. However, in kidneys with restricted function (< 35%), functional MRU underestimated the remaining renal function, with a mean difference of 6.6% and an SD of 24.4%. For evaluation of relevant urinary tract obstruction, the sensitivity of functional MRU was 100%, specificity was 81.6%, positive predictive value was 70.8%, and negative predictive value was 100%. CONCLUSION: Regarding split renal function, functional MRU shows a lack of accuracy in comparison with the clinical standard MAG3 scintigraphy, especially in patients with severely diminished function of one kidney. However, functional MRU allows an adequate assessment of urinary tract obstruction and a high-resolution morphologic evaluation of the whole urinary tract. Thus, functional MRU is suitable to add diagnostic value, especially as a complementary examination for complex individual cases in the presurgical state.

Proteinuria in children with autosomal dominant polycystic kidney disease.

BACKGROUND: Proteinuria is a common complication in adults with autosomal dominant polycystic kidney disease (ADPKD) and serves as a risk factor for progression. However, proteinuria has rarely been examined in children with ADPKD and the type of proteinuria has not yet been investigated. The aim of the study was to assess the prevalence and to analyse the types of proteinuria in children with ADPKD. METHODS: Children with ADPKD followed-up in our tertiary centres during the years 2012-2013 were investigated in a cross-sectional study. Morning urine was tested for total protein (PROT), albumin (ALB) and alpha-1-microglobulin (AMG). Renal function was assessed from serum creatinine as estimated glomerular filtration rate. RESULTS: Thirty-seven children of median age 11.2 (2.0-18.0) years were investigated. Median (range) PROT, ALB and AMG (in mg/mmol creatinine) were 15.1 (6.2-64.8), 2.54 (0.54-37.25) and 3.22 (0.04-10.16), respectively. Pathological total proteinuria (>22) was found in 30% of children, albuminuria (>2.2) in 49% of children and alpha-1-microglobulinuria (>0.55) in 65% of children. No correlation was found between PROT, ALB or AMG and office blood pressure, kidney size or estimated glomerular filtration rate. CONCLUSIONS: Proteinuria in children with ADPKD is a frequent finding, the most common type is tubular proteinuria. It should be measured in all ADPKD children.

Febrile urinary tract infection after pediatric kidney transplantation: a multicenter, prospective observational study.

BACKGROUND: Febrile urinary tract infections (fUTIs) are common after kidney transplantation (KTx); however, prospective data in a multicenter pediatric cohort are lacking. We designed a prospective registry to record data on fUTI before and after pediatric KTx. METHODS: Ninety-eight children (58 boys and 40 girls) ≤ 18 years from 14 mid-European centers received a kidney transplant and completed a 2-year follow-up. RESULTS: Posttransplant, 38.7% of patients had at least one fUTI compared with 21.4% before KTx (p = 0.002). Before KTx, fUTI was more frequent in patients with congenital anomalies of kidneys and urinary tract (CAKUT) vs. patients without (38% vs. 12%; p = 0.005). After KTx, fUTI were equally frequent in both groups (48.7% vs. 32.2%; p = 0.14). First fUTI posttransplant occurred earlier in boys compared with girls: median range 4 vs. 13.5 years (p = 0.002). Graft function worsened (p < 0.001) during fUTI, but no difference was recorded after 2 years. At least one recurrence of fUTI was encountered in 58%. CONCLUSION: This prospective study confirms a high incidence of fUTI after pediatric KTx, which is not restricted to patients with CAKUT; fUTIs have a negative impact on graft function during the infectious episode but not on 2-year graft outcome.

Automated Greulich-Pyle bone age determination in children with chronic kidney disease.

BACKGROUND: Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpert™ method with the manual assessment of an X-ray of the non-dominant hand. METHODS: In this retrospective multicenter study, 359 patients with CKD stages 2-5, aged 2-14.5 (girls) or 2.5-17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpert™. RESULTS: There was a strong correlation between the automatic and the manual method (r = 0.983, p < 0.001). The automatic method tended to generate higher bone age values (0.64 ± 0.73 years) in the younger patients (4-5 years) and to underestimate retardation or acceleration of bone age. The so-called "bone health index" (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (r = 0.12, p = 0.019). CONCLUSIONS: BoneXpert™ allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study.

Mutations in CYP24A1 and idiopathic infantile hypercalcemia.

BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence.

OBJECTIVE: Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. METHODS: Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. RESULTS: In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. CONCLUSION: The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways.

Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study.

BACKGROUND: The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS: In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS: EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 ± 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 ± 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS: Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.

Diagnosis of Alport syndrome--search for proteomic biomarkers in body fluids.

BACKGROUND: The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required. METHODS: Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays. RESULTS: The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies. CONCLUSIONS: These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

(Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation.

Epstein-Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV-related post-transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV-naïve pediatric renal transplant recipients (R-) who had received a graft from an EBV-positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1-year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high-risk pediatric kidney allograft recipients in the first year post-transplant. (ClinicalTrials.gov number: NCT00963248).

Microalbuminuria in children with primary and white-coat hypertension.

Microalbuminuria serves as an early marker of hypertension-related renal damage in adults. However, data on the prevalence of microalbuminuria in paediatric hypertensive patients in general and in children with white-coat hypertension (WCH) specifically are lacking. The aim of our study was to investigate the prevalence of microalbuminuria in children with primary hypertension (PH) and WCH, respectively. This was a retrospective case review of children with PH and WCH treated at three paediatric nephrology centres. Untreated children with either form of hypertension for whom measurements of urinary albumin excretion (UAE) had been performed were enrolled in the study. The study cohort comprised 52 children (39 boys) with hypertension (26 children with PH, 26 with WCH). Microalbuminuria (>3.2 mg/mmol creatinine) was present in 20% of children with PH and none of the children with WCH (p < 0.01). Children with PH had a higher median UAE than those with WCH (1.27 ± 1.92 vs. 0.66 ± 0.46 mg/mmol creatinine, p < 0.05). Based on these results, we suggest that children with PH have an increased prevalence of microalbuminuria, while children with WCH show no signs of hypertension-related renal damage.

Risk factors for renal insufficiency in children with urethral valves.

Posterior urethral valves (PUV) associated with renal dysplasia are one of the most common causes of end stage kidney disease (ESKD) in childhood. In order to identify risk factors for the progression of this condition to early renal failure, we have retrospectively analyzed the clinical course, renal function, and first postnatal renal ultrasound in a sample of 42 young male patients with PUV, who were followed at a single center. Twelve (28.6%) were diagnosed with ESKD at a median age of 11.3 years. Our comparison of PUV patients without decreased estimated glomerular filtration rate (eGFR) (group A; K/DOQI CKD stage 0-1) with PUV patients showing a decreased eGFR (group B; K/DOQI CKD stage 2-5) revealed the following significant risk factors for loss of eGFR: renal volume <3rd percentile (P < 0.001), elevated echogenicity (P = 0.001), pathologic corticomedullary differentiation (P < 0.001), >3 febrile urinary tract infections (P = 0.012), and decreased eGFR at 1 year of age (P < 0.001). Receiver operating characteristic curve analysis in the cohort confirms that patients showing a renal volume >88.2 ml/m(2) body surface area (BSA) are not at risk to develop K/DOQI CKD stage 5 (sensitivity 75%, specificity 77.3%, positive/negative predictive value 37.5/94.4%). Ultrasound promises to be a valuable tool for identifying endangered patients.

Novel developments in thrombotic microangiopathies: is there a common link between hemolytic uremic syndrome and thrombotic thrombocytic purpura?

Thrombotic microangiopathies (TMA) represent a spectrum of related disorders associated with newly formed thrombi that block perfusion and thus affect the function of either renal or neurological organs and tissue. Recent years have seen a dramatic development in the field of TMA and for the two major forms hemolytic uremic syndrome (HUS) and thrombocytopenic purpura (TTP), new genetic causes and also autoimmune forms have been identified. This development indicates a similar pathophysiology and suggests that the two acute disorders are based on common principles. HUS is primarily a kidney disease and TTP also develops in the kidney and at neurological sites. In HUS thrombi formation is likely due to a deregulated complement activation and inappropriate platelet activity. In TTP thrombi formation occurs because of inappropriate processing of released multimers of von Willebrand Factor (vWF). Defining both the similarities and the unique features of each disorder will open up new ways and concepts that are relevant for diagnosis, for therapy, and for the prognostic outcome of kidney transplantations. Here we summarize the most relevant topics and timely issues that were presented and discussed at the 4th International Workshop on Thrombotic Microangiopathies held in Weimar in October 2009 (www.hus-ttp.de).

Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation.

BACKGROUND: Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression. METHODS: The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months. RESULTS: Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%). CONCLUSION: Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.

Real-Time DMSA-SPECT/US Fusion Imaging Revealing Nonscarring Loss of Function After Pyelonephritis.

Using real-time SPECT/US fusion imaging, the localization of an uptake defect in DMSA scan could be identified unambiguously after being uncertain in ultrasound alone. Thereby, a localized functional loss, due to history of pyelonephritis, without scarring, but reduced cortical thickness could be verified. DMSA-SPECT/US primarily demonstrates its utility in depiction of renal pathologies and may be a descriptive tool in equivocal constellation of findings.

Estimated one-yr glomerular filtration rate is an excellent predictor of long-term graft survival in pediatric first kidney transplants.

Acute rejection episodes following pediatric renal transplantation have been progressively reduced by recent immunosuppressive regimens. Nevertheless, grafts continue to fail over time and surrogate parameters for long-term RGS are lacking. We investigated post-transplant renal function within the first yr as an independent predictor of long-term RGS in 104 pediatric first kidney transplant recipients (mean age 11.1 +/- 3.9 yr; mean follow-up 8.3 +/- 3.5 yr) transplanted between January 1989 and December 2000. GFR was assessed by use of the Schwartz formula at 30 days and six and 12 months after transplantation, respectively. Patients were further stratified at all times according to GFR: (i) GFR<45 mL/min/1.73 m(2), (ii) GFR 45-80 mL/min/1.73 m(2), and (iii) GFR>80 mL/min/1.73 m(2). Cox regression analysis including factors potentially influencing long-term RGS, e.g., age, gender, transplant yr, HLA-mismatch, underlying renal disease, clinical acute rejection, absolute GFR as well as the change in GFR within the first yr was performed. Graft failure occurred in 24 out of 104 patients (23%) 6.2 yr (mean) after transplantation corresponding to a cumulative five-yr graft survival of 87.5%. GFRs at 30 days and six and 12 months were significantly associated with long-term RGS in the univariate cox regression analysis (GFR at 30 days, p = 0.045; GFR at six months, p = 0.004; GFR at 12 months, p < 0.001). None of the other variables were significant parameters of correlation. Multivariate cox analysis revealed a GFR below 45 mL/min/1.73 m(2) at 12 months after transplantation as the only independent predictor of long-term RGS (hazard ratio 55.9, 95% CI 5.29-591, p = 0.001). GFR at 12 months post-transplant is an excellent surrogate parameter for long-term RGS in children. This parameter might be useful as a primary end-point in short-term pediatric clinical trials.

Angiotensin receptor blocker reduces proteinuria independently of blood pressure in children already treated with Angiotensin-converting enzyme inhibitors.

BACKGROUND/AIMS: Dual blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) has higher antiproteinuric effects than single blockade in adults. In children, little is known on dual blockade of the renin-angiotensin system. The study investigates whether adding an ARB to proteinuric children already on ACEI reduces proteinuria. METHODS: A total of 10 children (median age 13.3 years) with chronic kidney disease and persistent proteinuria despite maximal dose of ACEI were included. Losartan was given at an initial dose 0.8 mg/kg/day. Proteinuria, blood pressure (BP) and renal function (glomerular filtration rate) were measured. RESULTS: Mean proteinuria decreased from 484 +/- 290 mg/mmol creatinine to 223 +/- 197 after 1-3 months of losartan treatment and remained stable at 234 +/- 153, 224 +/- 177 and 195 +/- 133 after 3-6, 6-12 months and at the last follow-up check (median 1.9 years, p < 0.05 for all visits vs. before treatment). The median percentage decrease in proteinuria was 66, 56, 44 and 66% during the study periods. No significant change in BP, glomerular filtration rate or serum potassium was observed. One child complained of rash, which led to discontinuation of losartan. CONCLUSION: Adding an ARB to current ACEI treatment can further reduce proteinuria in children with chronic kidney disease without affecting BP.