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Background Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4- to 8- week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5- to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation. Methods/design The subjects will be 300 children with relapsing SSNS (⩾2 relapses in preceding year), who will be randomised to receive either a 6-day course of daily prednisolone or no change to their current therapy (with the use of placebo to double blind) each time they develop an URTIover 12 months. A strict definition for URTI will be used. Subjects will be reviewed at 3, 6, 9 and 12 months to capture data regarding relapse history, ongoing therapy and adverse effect profile, including behavioural problems and quality of life. A formal health economic analysis will also be performed. The primary end point of the study will be the incidence of URTI-related relapse (3 days of Albustix +++) following the first infection during the 12- month follow-up period. DNA and RNA samples will be collected to identify a potential genetic cause for the disease. Subjects will be recruited from over 100 UK centres with the assistance of the Medicines for Children Research Network. PREDNOS 2 is funded by the National Institute for Health Research Health Technology Assessment Programme (11/129/261) Discussion We propose that PREDNOS 2 will be a pivotal study that will inform the future standard of care for children with SSNS. If it is possible to reduce the disease relapse rate effectively and safely, this will reduce the morbidity and cost associated with drug treatment, notwithstanding hospital admission and parental absence from employment. Trial registration Current Controlled Trials (ISRCTN10900733). [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers delay progression of chronic kidney disease and have antiproteinuric effects beyond their effects on blood pressure. They are routinely used in adults; however, their efficacy and safety in children, in whom the causes of chronic kidney disease are significantly different relative to adults, is uncertain. Here we assessed an open-label extension of a previous 3-month blinded trial, in which the efficacy and tolerability of losartan was compared to placebo or amlodipine in 306 normotensive and hypertensive children with proteinuria. In this study, 268 children were re-randomized to losartan or enalapril and followed until 100 patients completed 3 years of follow-up for proteinuria and renal function. The least squares percent mean reduction from baseline in the urinary protein/creatinine ratio was 30.01% for losartan and 40.45% for enalapril. The least squares mean change from baseline in eGFR was 3.3 ml/min per 1.73 m2 for losartan and 7.0 ml/min per 1.73 m2 for enalapril. The incidence of specific adverse events such as hyperkalemia and renal dysfunction was low and similar in both groups. Both were generally well tolerated and, overall, fewer drug-related adverse events occurred with losartan than with enalapril. Thus, in children with proteinuria, losartan and enalapril significantly reduced proteinuria without any appreciable changes in eGFR, effects that were maintained throughout the study. Both losartan and enalapril were generally well tolerated. [ABSTRACT FROM AUTHOR]

Grenda R, Webb NJA. Steroid minimization in pediatric renal transplantation: Early withdrawal or avoidance? Pediatr Transplantation 2010: 14:961-967. © 2010 John Wiley & Sons A/S. Clinically important adverse events associated with the use of corticosteroids post-transplantation include hypertension, dyslipidemia, impaired glucose metabolism (including diabetes mellitus), growth retardation, bone fractures, and cosmetic problems. Over recent years, a number of studies have investigated the effect of minimizing exposure to corticosteroids in post-transplant immunosuppression protocols in both adults and children. In pediatric patients, several different approaches have been evaluated, including late steroid withdrawal, early steroid withdrawal, and complete steroid avoidance with or without poly- or monoclonal antibody induction and a variety of maintenance immunosuppressants. This manuscript reviews the key studies and documents the specific clinical benefits associated with steroid minimization. The development of PTLD and bone marrow suppression has been a major safety concern in some of these studies. These studies and other adverse effects are discussed. [ABSTRACT FROM AUTHOR]

The aims of this study were (1) to ascertain ciclosporin C2 levels currently being achieved in children with steroid-sensitive nephrotic syndrome (SSNS) and renal transplants (RTs), (2) to determine the feasibility of the use of finger-prick samples for the measurement of ciclosporin levels, and (3) to identify any correlation between hypertrichosis or gingival overgrowth (GO) and level of ciclosporin 2 h post-dose (C2). Seventy-two children (39 with SSNS, 33 with RT) participated. Ciclosporin 12 h trough (C12) and C2 levels were measured in venous and finger-prick samples by high-performance liquid chromatography tandem mass spectroscopy. Photographs of the teeth and back were taken for assessment of GO and hypertrichosis. Mean (±SD) C2 levels in the SSNS and RT groups were 512 (±181) μg/l and 471 (±229) μg/l. There was a highly significant relationship between venous and finger-prick ciclosporin levels (r2 = 0.96, P < 0.0001). Fourteen children had severe GO. There was a small, though statistically significant, impact of ciclosporin level on GO (C2 r2 = 0.12, P = 0.003 and C12 r2 = 0.06, P = 0.038) but no correlation with dose (milligrammes per kilogramme per day or milligrammes per square metre per day) or duration. Seventeen children had moderate or severe hypertrichosis, this being more common in children of South Asian ethnicity ( P < 0.0001). There was no correlation between ciclosporin exposure or duration and hypertrichosis. Finger-prick blood sampling may serve as a practical alternative to venepuncture in children receiving ciclosporin. [ABSTRACT FROM AUTHOR]

Living kidney donation by minors is an infrequently performed although highly controversial procedure. This manuscript reports the frequency of this practice in North America, Europe, Australia and New Zealand. The relevant laws and professional guidelines are reviewed and the ethical considerations discussed. [ABSTRACT FROM AUTHOR]

Regular monitoring of tacrolimus levels is an essential component of post-transplantation follow up in children receiving this drug. We have developed a high performance liquid chromatography tandem mass spectrometry (HPLC T-MS) methodology which measures whole blood tacrolimus levels using a 10 μL sample, thus allowing the use of fingerprick blood sampling. The aim of this study was to determine the degree of relationship between fingerprick and venous tacrolimus levels measured by HPLC T-MS and venous levels measured using the Abbott IMx tacrolimus II assay (IMx). This has not previously been investigated. Blood samples were collected from children on five separate occasions. In addition to the routine venous IMx sample, a further venous and fingerprick sample were collected for tacrolimus level measurement by HPLC T-MS. These were mailed to the central laboratory. One hundred and seventy-two sets of triplicate samples were collected from 36 children (33 kidney, two kidney–pancreas and one kidney–heart). Linear regression analysis showed highly significant relationships between HPLC T-MS venous and IMx venous levels (r2 = 0.83), HPLC T-MS fingerprick and HPLC T-MS venous levels (r2 = 0.85) and HPLC T-MS fingerprick and IMx venous levels (r2 = 0.71) (all p < 0.0001). Bland Altman analysis showed a small, although statistically significant difference between measured values, fingerprick HPLC T-MS levels being lower than venous IMx levels, the mean difference being 0.58 ng/mL (95% CI 0.26–0.91, t = 3.54, d.f. = 168, p = 0.0005 one sample t-test). Precise conversion between the two techniques could be achieved using the regression formula; IMx venous level = 0.751 + 0.978. HPLC T-MS fingerprick level. There is a strong significant relationship between fingerprick blood tacrolimus levels measured by HPLC T-MS and venous blood levels measured by IMx, allowing the two to be used interchangeably for routine clinical purposes. [ABSTRACT FROM AUTHOR]

Filler G, Webb NJA, Milford DV, Watson AR, Gellermann J, Tyden G, Grenda R, Vondrak K, Hughes D, Offner G, Griebel M, Brekke IB, McGraw M, Balzar E, Friman S, Trompeter R. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplantation 2005. © 2005 Blackwell Munksgaard This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m2) was 64.9 ± 20.7 (n = 84) vs. 57.8 ± 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 ± 19.8 (n = 71) vs. 51.7 ± 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 ± 26.4 (n = 81) vs. 53.0 ± 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 ± 22.9 (n = 51) vs. 53.0 ± 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome. [ABSTRACT FROM AUTHOR]

Heparanase activity is dysregulated in children with steroid-sensitive nephrotic syndrome.Background.Immune cells express heparanase, an endoglycosidase, able to degrade heparan sulfate glycosaminoglycan (HSGAG) in the glomerular capillary wall (GCW) and potentially induce proteinuria. The aim of this study was to determine whether dysregulated heparanase expression is associated with the heavy proteinuria of childhood steroid-sensitive nephrotic syndrome (SSNS).Methods.Plasma and urinary heparanase activity and peripheral blood mononuclear cell (PBMC) mRNA heparanase levels[real-time polymerase chain reaction (PCR)] were measured in children with SSNS in relapse and remission. Plasma and urinary heparanase activity was determined in adult patients with nephrotic syndrome and in age- and gender-matched controls.Results.Plasma heparanase activity was reduced in SSNS with relapse (811.2 units) compared to remission (1147.96 units) (P= 0.003) and control subjects (1390.51 units) (P<0.001). In adult nephrotic syndrome, plasma heparanase activity was significantly lower in patients compared to controls. However, there was no difference between remission and relapse states. In children, urinary heparanase activity/urinary creatinine ratio was highest in SSNS relapse (14.26 units/mg) compared with remission (7.43 units/mg) (P= 0.016) and controls (2.29) (P<0.001). However, PBMC heparanase mRNA expression was not different between these three groups. In adult nephrotic syndrome, urinary heparanase activity/urinary creatinine levels were lower in both remission and relapse compared to controls and there was no difference between remission and relapse states.Conclusion.In childhood SSNS, there is a qualitative and quantitative difference in urinary heparanase activity expression that is not paralleled in adult nephrotic syndrom. These data suggest that dysregulated heparanase expression may play a significant role in the pathogenesis of SSNS, possibly through an abnormality in post-translational control of latent heparanase activation. [ABSTRACT FROM AUTHOR]

Effective antibody removal using PE, DFPP and IA has led to increased access to live donor organs through ABOi RT for patients with chronic kidney disease. However, there have been no head-to-head comparator studies between these modalities, and the choice of technique is usually influenced by cost and institutional preference. We describe the clinical course of a child undergoing ABOi RT, in whom IA without preconditioning with rituximab did not achieve a satisfactory reduction in the antibody titers, who went on to have a successful living donor RT following rituximab and DFPP. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children. Methods: We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR. Results: SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months. Conclusions: Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria. [ABSTRACT FROM AUTHOR]

Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month–6 years (stratified: 4–6 years, 2–<4 years, 1–<2 years, 6–<12 months, and 1–<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as "pleasant/neutral" in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1–<6-months group was stopped early due to coughing—evaluated as "choked on" in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children. [ABSTRACT FROM AUTHOR]

Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4- to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5- to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.Methods/design: The subjects will be 300 children with relapsing SSNS (≥2 relapses in preceding year), who will be randomised to receive either a 6-day course of daily prednisolone or no change to their current therapy (with the use of placebo to double blind) each time they develop an URTI over 12 months. A strict definition for URTI will be used. Subjects will be reviewed at 3, 6, 9 and 12 months to capture data regarding relapse history, ongoing therapy and adverse effect profile, including behavioural problems and quality of life. A formal health economic analysis will also be performed. The primary end point of the study will be the incidence of URTI-related relapse (3 days of Albustix +++) following the first infection during the 12-month follow-up period. DNA and RNA samples will be collected to identify a potential genetic cause for the disease. Subjects will be recruited from over 100 UK centres with the assistance of the Medicines for Children Research Network.PREDNOS 2 is funded by the National Institute for Health Research Health Technology Assessment Programme (11/129/261).Discussion: We propose that PREDNOS 2 will be a pivotal study that will inform the future standard of care for children with SSNS. If it is possible to reduce the disease relapse rate effectively and safely, this will reduce the morbidity and cost associated with drug treatment, notwithstanding hospital admission and parental absence from employment.Trial Registration: Current Controlled Trials (ISRCTN10900733). [ABSTRACT FROM AUTHOR]

Urinary tract infection is a common bacterial infection of childhood. Renal parenchymal scarring, a recognised complication of urinary tract infection, is responsible for up to 24% of children entering end-stage renal failure. Why acute inflammation results in renal scarring in some children whilst in others complete resolution occurs without scarring is at present poorly understood. This article reviews the role of the cytokines, adhesion molecules and growth factors in the inflammatory response during acute pyelonephritis and renal parenchymal scarring. We hypothesize that inter-individual variability in cellular response may in part be responsible for this variable clinical outcome. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Cystinosis, a rare autosomal recessive lysosomal storage disorder, results in an abnormal accumulation of the amino acid cystine in multiple organs and tissues of the body. Renal symptoms typically develop in the first few months of life, with extra-renal manifestations becoming apparent over the next 10–20 years, which require coordinated multidisciplinary care. Here, we describe a consensus-based guidance to support the management of adolescents and adults living with cystinosis. The programme was led by a Steering Committee (SC) of six experts in the management of patients with cystinosis, who identified a list of 15 key questions reflecting the multi-organ effects of cystinosis. An Extended Faculty (EF) of eight additional specialists was invited to answer the questions via an online digital platform using a quasi-Delphi approach. The consolidated answers were summarized into recommendations. Where evidence was lacking, recommendations were developed using collective expert consensus. The EF was asked to agree/disagree with the clinical recommendations. The expert-agreed clinical recommendations provide guidance that considers both renal and extra-renal systems. The topics covered are advice on fertility and family planning, consideration of the nervous, muscular, ophthalmic, cardio-respiratory, endocrine, dermatological and gastrointestinal systems, as well as guidance on dental care, diet, lifestyle, and improving quality of life and psychological well-being. In summary, this work outlines recommendations and a checklist for clinicians with a vision for improving and standardizing the multidisciplinary care for patients with cystinosis. [ABSTRACT FROM AUTHOR]

There are limited data regarding the presence of DSAs and their effect on graft function in pediatric renal transplantation. The role for serial DSA monitoring in routine clinical practice is unclear. All patients attending a regional transplant clinic were tested for DSAs, measured using Luminex single/mixed antigen beads. Any patient having a positive result subsequently underwent historic testing on samples previously obtained. DSA-positive patients underwent prospective monitoring of DSAs, and correlation with clinical events was studied. Nine of a total of 50 patients (18%) were DSA-positive, of whom six had graft dysfunction. The DSA-positive cohort had significantly increased episodes of AR (p = 0.01). There were two graft losses in the DSA-positive group and none in the DSA-negative group. Eight of the DSA-positive group had potentially reduced exposure to IS because of either adherence issues or clinical indications. DSAs were associated with increased risk of rejection. There appears to be a role for serial monitoring of DSAs in patients where there has been a reduced exposure to IS so that early intervention with optimized IS can be considered. [ABSTRACT FROM AUTHOR]

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome. Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results. Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known: • Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate. • Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New: • The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome. • Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Summary: There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels. [ABSTRACT FROM AUTHOR]

Tacrolimus granules were developed for patients who are unable to swallow capsules. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, which is based on Ctrough for tacrolimus capsules. Pharmacokinetic (PK) data for tacrolimus granules are required to establish the basis for TDM in those who are unable to swallow capsules. In this phase IV study (NCT01371331) of children undergoing liver, kidney, or heart transplantation, patients received tacrolimus granules 0.15 mg/kg twice daily; first dose was administered within 24 hours of reperfusion. PK analysis samples were collected after reperfusion, after first dose of tacrolimus (Day 1), and at steady state (Day 7; >4 days stable dose). Of the 52 transplant recipients enrolled, 38 had two evaluable PK profiles. Mean AUCtau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUCtau at steady state was 195, 208, and 165 hour*ng/mL. Ctrough and AUCtau were positively correlated after first dose of tacrolimus and at steady state (Pearson's coefficients: r = 0.81 and r = 0.87, respectively). This study demonstrated that Ctrough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations. [ABSTRACT FROM AUTHOR]

Background: Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse.Methods: We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA.Results: Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure.Conclusions: Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA. [ABSTRACT FROM AUTHOR]

Background: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication.Methods: In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children.Results: The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033).Conclusions: These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses. [ABSTRACT FROM AUTHOR]

Background: The Paediatric Quality of Life Inventory (PedsQL™) questionnaire is a widely used, generic instrument designed for measuring health-related quality of life (HRQoL); however, it is not preference-based and therefore not suitable for cost-utility analysis. The Child Health Utility Index-9 Dimension (CHU-9D), however, is a preference-based instrument that has been primarily developed to support cost-utility analysis.Objective: This paper presents a method for estimating CHU-9D index scores from responses to the PedsQL™ using data from a randomised controlled trial of prednisolone therapy for treatment of childhood corticosteroid-sensitive nephrotic syndrome.Methods: HRQoL data were collected from children at randomisation, week 16, and months 12, 18, 24, 36 and 48. Observations on children aged 5 years and older were pooled across all data collection timepoints and were then randomised into an estimation (n = 279) and validation (n = 284) sample. A number of models were developed using the estimation data before internal validation. The best model was chosen using multi-stage selection criteria.Results: Most of the models developed accurately predicted the CHU-9D mean index score. The best performing model was a generalised linear model (mean absolute error = 0.0408; mean square error = 0.0035). The proportion of index scores deviating from the observed scores by <  0.03 was 53%.Conclusions: The mapping algorithm provides an empirical tool for estimating CHU-9D index scores and for conducting cost-utility analyses within clinical studies that have only collected PedsQL™ data. It is valid for children aged 5 years or older. Caution should be exercised when using this with children younger than 5 years, older adolescents (>  13 years) or patient groups with particularly poor quality of life.Isrctn Registry No: 16645249. [ABSTRACT FROM AUTHOR]

Background: Because infections constitute a major cause of morbidity and mortality in paediatric renal allograft recipients, avoidance of preventable systemic infections by vaccination before transplantation is of utmost importance. However, data on the completeness of vaccinations and factors associated with incomplete vaccination coverage are scarce. Methods: Within the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national, retrospective study investigating the vaccination coverage before transplantation of 254 European children with end-stage renal disease (mean age 10.0 ± 5.6 years). Results: Only 22 out of 254 patients (8.7%) presented complete vaccination coverage. In particular, the respective vaccination coverage against human papillomavirus (27.3%), pneumococci (42.0%), and meningococci (47.9%) was low. Patients with complete pneumococcal vaccination coverage had numerically less lower respiratory tract infections during the first 3 years post-transplant than children without vaccination or with an incomplete status (16.4% vs 27.7%, p = 0.081). Vaccine-preventable diseases post-transplant were 4.0 times more frequently in unvaccinated than in vaccinated patients. Factors associated with an incomplete vaccination coverage were non-Caucasian ethnicity (OR 9.21, p = 0.004), chronic dialysis treatment before transplantation (OR 6.18, p = 0.001), and older age at transplantation (OR 1.33, p < 0.001). Conclusions: The vaccination coverage in paediatric kidney transplant candidates is incomplete. Paediatric nephrologists, together with primary-care staff and patients' families, should therefore make every effort to improve vaccination rates before kidney transplantation. [ABSTRACT FROM AUTHOR]

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non-modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post-transplant. Low estimated glomerular filtration rate at 1 year post-transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three- and 25-fold ( P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile. [ABSTRACT FROM AUTHOR]

Background: Children with chronic kidney disease (CKD), requiring dialysis or kidney transplantation, have a mortality rate of up to 30-fold higher than the general aged-matched population, and severely impaired quality of life. Symptoms such as fatigue and pain are prevalent and debilitating. Children with CKD are at risk of cognitive impairment, and poorer educational, vocational, and psychosocial outcomes compared with their well peers, which have consequences through to adulthood. Treatment regimens for children with CKD are long-term, complex, and highly intrusive. While many trials have been conducted to improve outcomes in children with CKD, the outcomes measured and reported are often not relevant to patients and clinicians, and are highly variable. These problems can diminish the value of trials as a means to improve the lives of children with CKD. The Standardised Outcomes in Nephrology-Children and Adolescents (SONG-Kids) study aims to develop a core outcome set for trials in children and adolescents with any stage of CKD that is based on the shared priorities of all stakeholders.Methods/design: SONG-Kids involves five phases: a systematic review to identify outcomes (both domains and measures) that have been reported in randomised controlled trials involving children aged up to 21 years with CKD; focus groups (using nominal group technique) with adolescent patients and caregivers of paediatric patients (all ages) to identify outcomes that are relevant and important to patients and their family and the reasons for their choices; semistructured key informant interviews with health professionals involved in the care of children with CKD to ascertain their views on establishing core outcomes in paediatric nephrology; an international three-round online Delphi survey with patients, caregivers, clinicians, researchers, policy-makers, and members from industry to develop consensus on important outcome domains; and a stakeholder workshop to review and finalise the set of core outcome domains for trials in children with CKD (including nondialysis-dependent, dialysis, and kidney transplantation).Discussion: Establishing a core outcome set to be reported in all trials conducted in children with any stage of CKD will enhance the relevance, transparency, and impact of research to improve the lives of children and adolescents with CKD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Vitamin D insufficiency and hyperparathyroidism in children with chronic kidney disease," by S. Menon and colleagues.

Background: Few evidence-based, on-line resources exist to support home-based care of childhood long-term conditions.Methods: In a feasibility study, children with stages 3, 4, or 5 chronic kidney disease, parents and professionals collaboratively developed a novel Online Parent Information and Support (OPIS) application. Parents were randomized to an intervention arm with access to OPIS or a control arm without access. OPIS usage was assessed using Google Analytics. Parents in the intervention arm completed the Suitability Assessment of Materials (SAM) and User Interface Satisfaction (USE) questionnaires and participated in qualitative interviews.Results: Twenty parents accessed OPIS with a mean of 23.3 (SD 20.8, range 2-64) visits per user. Responses from the SAM and USE questionnaires were positive, most respondents rating OPIS highly and finding it easy to use. Qualitative suggestions include refinement of OPIS components, enabling personalization of OPIS functionalities and proactive endorsements of OPIS by professionals.Conclusions: Implementation of OPIS into standard practice is feasible in the centre where it was developed. Suggested developments will augment reported strengths to inform ongoing testing in the wider UK network of units. Our design and methods are transferrable to developing and evaluating web-applications to support home-based clinical care-giving for other long-term conditions. [ABSTRACT FROM AUTHOR]

The article reports that British Committee for Standards in Haematology has issued guidelines for patients with hematological malignancies for the management of tumour lysis syndrome. Topics include risk factors for tumour lysis syndrome including high tumour burden with rapid cell turnover, treatment of tumour lysis syndrome by maintaining fluid balance and management of hyperuricaemia.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes. [ABSTRACT FROM AUTHOR]

This retrospective study investigated the outcome of 27 children (19 male) with Henoch-Schönlein purpura nephritis (HSN) of International Study of Kidney Disease in Children (ISKDC) grade 3b or higher treated with long-term immunosuppressive therapy in a single centre over a 10-year period. The mean age at presentation was 9.7 years. The median estimated glomerular filtration rate (eGFR) was 91.3 ml/min per 1.73 m2, with the median urine protein creatinine ratio (UP:UC) 556 mg/mmol. The treatment protocol comprised daily steroids and cyclophosphamide for 8–12 weeks followed by azathioprine and a reducing regimen of alternate-day steroids for 8–12 months. After a mean follow-up period of 7 years following presentation, 37% made a complete recovery, 40.7% had persistent proteinuria, 7.4% had persistent proteinuria and were on antihypertensive therapy and 14.8% had progressed to end-stage kidney failure (ESKF). Children with poor outcome were older at presentation ( p 0.005), had more crescents ( p 0.015) and had heavier proteinuria 6 months post initial biopsy ( p 0.023). All of the four children with ESKF had nephrotic range proteinuria and greater than 50% crescents on initial biopsy. Despite long-term immunosuppression, the majority of children with HSN grade 3b or higher will have persistent renal abnormalities on long-term follow-up. [ABSTRACT FROM AUTHOR]

Background. Children with minimal change nephrotic syndrome (MCNS) receive repeated courses of high dose oral prednisolone. No previous study has investigated the impact of this on final bone mineral density (BMD). Young adults previously reported in a large follow-up study of children with MCNS were invited to participate in a cross-sectional study. Areal BMD (aBMD) of the spine (L1-4), left femoral neck, and total left hip was measured using dual x-ray absorptiometry (DXA), and volumetric BMD (vBMD) of the distal radius was measured by pQCT. BMD results were compared with reference data provided by the manufacturers of the densitometers. Methods. Thirty-four (24 male) of the original cohort of 62 participated in the study. The mean (SD) final height Z score of the cohort was –0.45 (0.92) ( P= 0.007) and mean BMI Z score 1.62 (1.53) ( P < 0.0001). Results. There was a highly significant reduction in distal radial trabecular vBMD; the mean Z score was –0.95 (0.99) and T score –1.04 (1.01) (both P < 0.0001); however, there was no reduction in distal radial total vBMD, the mean Z score being 0.00 (0.95) and T score −0.08 (0.99), ( P= 0.99 and 0.66, respectively). The aBMD of the lumbar spine and femoral neck also showed a reduction in T scores [−0.45 (1.27), P= 0.045 and −0.49 (0.86), P= 0.002, respectively], but not Z scores [−0.37 (1.28) and −0.15 (0.87), respectively, both P= NS]. Total hip aBMD was not different from the control population. Conclusion. Adult survivors of childhood MCNS have a significant reduction in forearm trabecular vBMD, placing them at increased fracture risk at this site. [ABSTRACT FROM AUTHOR]

Background and aims: This multicenter trial compared immediate‐release tacrolimus (IR‐T) vs prolonged‐release tacrolimus (PR‐T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow‐up efficacy and safety results are reported herein. Materials and methods: Patients, randomized 1:1, received once‐daily, PR‐T or twice‐daily, IR‐T within 4 days of surgery. After a 4‐week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy‐confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. Results: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR‐T and IR‐T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR‐T n = 1; IR‐T n = 7). Conclusions: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR‐T‐based immunosuppression is effective and well tolerated to 1‐year post‐transplantation. [ABSTRACT FROM AUTHOR]

Focuses on a study that examined how auditing against a standard for Hepatitis B patient and pediatric nephrology staff screening improved quality of care and reduced risks. Significance of clinical audit; Methodology; Results and conclusion.

This study was a Phase II, open‐label, multicenter, single‐arm, cross‐over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate‐release tacrolimus (IR‐T) to prolonged‐release tacrolimus (PR‐T). In Days −30 to −1 of screening period, patients received their IR‐T‐based regimen; during Days 1‐7, patients received study IR‐T (same dose as screening). On Day 7, the first 24‐hours PK profile was taken; patients were then converted to PR‐T (1 mg:1 mg), with a second 24‐hours PK profile taken on Day 14. The primary end‐point was tacrolimus area under the blood concentration–time curve over 24 hours (AUC24); secondary end‐points were maximum concentration Cmaxand concentration at 24 hours C24. The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%‐125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR‐T:IR‐T LSM ratio (90% CI) was similar overall for AUC24, max, and C24, and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24, and between PR‐T and IR‐T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR‐T to PR‐T at the same total daily dose, using the same therapeutic drug monitoring method. [ABSTRACT FROM AUTHOR]

Phase 2, parallel‐group, multicenter, open‐label, 4‐week study, comparing PK of PR‐T vs IR‐T in de novo pediatric patients undergoing primary kidney, liver, or heart transplantation. Patients randomized 1:1 to receive once daily, PR‐T‐, or twice‐daily, IR‐T‐based regimens; dose adjustments permitted after Day 1. Twenty‐four‐hour PK profiles collected on Days 1, 7, and 28. Primary endpoint: tacrolimus AUC24. Secondary end points included tacrolimus C24 and Cmax. Endpoints compared between PR‐T and IR‐T on Days 1, 7, and 28. Predefined similarity interval for CIs of LSM ratios: 80%‐125%. PK analysis set comprised 33 patients (PR‐T, n = 15; IR‐T, n = 18). Overall, AUC24 and Cmax were lower on Day 1 vs 7 and 28. Geometric LSM ratios of PR‐T:IR‐T on Days 1, 7, and 28 were 66.3%, 92.5%, 99.9%, respectively, for AUC24; 66.3%, 82.2%, 90.9% for C24; and 77.3%, 120.3%, 92.2% for Cmax. AUC24 90% CI within predefined similarity interval on Day 28; other 90% CIs fell outside. Linear relationship was similar between AUC24 and C24, and between tacrolimus formulations, suggesting that the same therapeutic drug monitoring method can be used with both formulations in de novo pediatric allograft recipients. [ABSTRACT FROM AUTHOR]

A response by the authors to a letter to the editor on their article about the published guidelines for the management of tumour lysis syndrome is presented.

Background: Limited negotiation around care decisions is believed to undermine collaborative working between parents of children with long-term conditions and professionals, but there is little evidence of how they actually negotiate their respective roles. Using chronic kidney disease as an exemplar this paper reports on a multi-method study of social interaction between multidisciplinary teams and parents as they shared clinical care.Methods: Phases 1 and 2: a telephone survey mapping multidisciplinary teams' parent-educative activities, and qualitative interviews with 112 professionals (Clinical-psychologists, Dietitians, Doctors, Nurses, Play-specialists, Pharmacists, Therapists and Social-workers) exploring their accounts of parent-teaching in the 12 British children's kidney units. Phase 3: six ethnographic case studies in two units involving observations of professional/parent interactions during shared-care, and individual interviews. We used an analytical framework based on concepts drawn from Communities of Practice and Activity Theory.Results: Professionals spoke of the challenge of explaining to each other how they are aware of parents' understanding of clinical knowledge, and described three patterns of parent-educative activity that were common across MDTs: Engaging parents in shared practice; Knowledge exchange and role negotiation, and Promoting common ground. Over time, professionals had developed a shared repertoire of tools to support their negotiations with parents that helped them accomplish common ground during the practice of shared-care. We observed mutual engagement between professionals and parents where a common understanding of the joint enterprise of clinical caring was negotiated.Conclusions: For professionals, making implicit knowledge explicit is important as it can provide them with a language through which to articulate more clearly to each other what is the basis of their intuition-based hunches about parents' support needs, and may help them to negotiate with parents and accelerate parents' learning about shared caring. Our methodology and results are potentially transferrable to shared management of other conditions. [ABSTRACT FROM AUTHOR]