The causes and consequences of paediatric kidney disease on adult nephrology care.

Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

Short courses of daily prednisolone during upper respiratory tract infections reduce relapse frequency in childhood nephrotic syndrome.

BACKGROUND: Relapses of childhood nephrotic syndrome (NS) are frequently precipitated by viral upper respiratory tract infections (URTIs). A review of the literature reveals that in patients with steroid-dependent NS on alternate day corticosteroids, a short course of daily corticosteroid therapy during the course of an URTI may reduce relapse frequency. OBJECTIVE: To assess the effect of a short course of low-dose corticosteroid therapy during the course of an URTI on relapse frequency in patients with steroid-sensitive NS who have not been taking any treatment for a minimum period of 3 months. METHODS: A double-blind placebo-controlled crossover trial was conducted on 48 patients with idiopathic NS who had not been receiving corticosteroid therapy for a minimum of 3 months. Patients were randomized into two groups. Group A received 5 days of daily prednisolone at 0.5 mg/kg at the onset of an URTI while group B received 5 days of placebo. Both groups were followed up for 1 year and the URTI-induced relapse frequency was noted. A crossover was performed during the next year, with group A receiving placebo and group B receiving prednisolone. RESULTS: Thirty-three patients completed the study. In the treatment group, 115 episodes of URTI led to 11 relapses while in the control group 101 episodes of URTI led to 25 relapses. There was no significant difference between the mean number of URTIs between the treatment and control groups. The treatment group had significantly less relapses compared to the control group (p = 0.014). Within the treatment group, 65.6% did not relapse, while the remainder had a single relapse. In contrast, only 40.6% of the control group remained in remission while 40.6% suffered a single relapse and 18.8% had two or more relapses. CONCLUSIONS: Prescribing a short course of daily corticosteroids during an URTI significantly reduces the frequency of URTI-induced relapse in patients with steroid-responsive NS who are off corticosteroid therapy.

Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years.

BACKGROUND: Nephrotic syndrome (NS) presenting early in life is caused by heterogeneous glomerular diseases. We retrospectively evaluated whether histological diagnosis in children presenting with NS in the first year of life predicts remission or progression to end-stage kidney disease (ESKD). METHODS: This is a single centre retrospective review of all children diagnosed with NS before one year of age between 1990 and 2009. All subjects had a renal biopsy, which was independently blindly reviewed by a single renal pathologist for the purpose of this study. RESULTS: Forty-nine children (25 female) who presented at 0.1-11.6 (median 1.6) months were included with 31 presenting within the first three months of life. Histopathological review diagnostic categories were; 13 Mesangial proliferative glomerulopathy (MesGN), 12 Focal and segmental glomerulosclerosis (FSGS), 11 Finnish type changes, eight Diffuse Mesangial Sclerosis (DMS), three Minimal change disease (MCD) and one each of Dense Deposit Disease (DDD) and Membranous nephropathy. Two children died from haemorrhagic complications of the biopsy. Eight children achieved remission (four MesGN, one Finnish type changes, one FSGS, one MCD and one membranous) with patient and renal survival of 73 % and 43 %, respectively, at follow-up duration of 5-222 (median 73) months (with five lost to follow-up). All children with Finnish-type histopathological changes presented within five months of age. Due to the historical nature of the cohort, genetic testing was only available for 14 children, nine of whom had an identifiable genetic basis (seven NPHS1, one PLCE1 and one ITGA3) with none of these nine children achieving remission. All of them had presented within four months of age and required renal replacement therapy, and two died. CONCLUSIONS: Histopathological findings are varied in children presenting with NS early in life. Whilst groups of histological patterns of disease are associated with differing outcomes, accurate prediction of disease course in a specific case is difficult and more widespread genetic testing may improve the understanding of this group of diseases and their optimal management.

Nephrotic syndrome in infancy can spontaneously resolve.

Nephrotic syndrome in the first year of life (NSFL) is a heterogeneous group of disorders, the management of which is supportive, as most patients do not respond to immunosuppression. Prognosis is guarded, as the syndrome tends to lead to end-stage renal failure. We describe four cases, all of which went into spontaneous remission. These patients had severe nephrosis that began postnatally at ages 15 days to 7 months and had preceding symptoms of viral infections. One infant had proven pertussis and required ventilation for respiratory failure. Renal biopsies showed varying degrees of mesangial expansion and increased cellularity. Two biopsies showed mild mesangial sclerosis and the other two only scattered globally sclerosed glomeruli. Supportive treatment was started with 20% albumin infusions, diuretics, penicillin, and thyroxine. Angiotensin-converting enzyme (ACE) inhibitors were used to reduce proteinuria in all infants, and one was also treated with indomethacin. The nephrosis gradually resolved, and protein-lowering medications were successfully weaned completely 5-30 months after presentation. The patients were protein free with normal renal function at last follow-up. Investigations including viral studies and autoimmune profiles were negative. Genetic studies for NPHS1, NPHS2, WT1, and LAM-ß were negative. We therefore describe a subgroup of NSFL with good prognosis associated with infectious prodromes. This is also the first-described case of pertussis causing nephrotic syndrome.

HNF1B mutations associate with hypomagnesemia and renal magnesium wasting.

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss.

Recent studies have suggested adverse outcome for renal allograft rejection associated with dense CD20 lymphocytic infiltrates in transplant renal biopsies. We investigated further the relationship between renal allograft survival and CD20+ lymphocytic infiltrates in renal transplant biopsies from children with graft dysfunction. Fifty consecutive unselected renal transplant biopsies were performed for investigation of acute, chronic or acute on chronic renal allograft dysfunction in 48 children aged 1-17 (median 13.1) years, at 0-155 (median 22) months post-transplantation with median follow up of 24 months post-biopsy. Seventeen (35%) graft losses occurred at 1-163 (median 49) months post-transplantation. There was increased graft loss in those with dense (>300 cells/hpf) CD20+ lymphocytic infiltrates present on biopsy (p = 0.043). Dense B-cell infiltrates were also associated with increased glucocorticoid requirement in those with acute cellular rejection (p = 0.0015). There were no significant differences in age, sex, HLA-mismatch, type of transplantation, EBV or CMV serology or baseline immunosuppressive regimens between those with or without dense CD20+ infiltrates. Dense CD20+ lymphocytic infiltrates in renal transplant biopsies are associated with adverse clinical outcome, including increased graft loss. This observation raises the possibility of future studies examining the efficacy of B cell depletion therapy in this clinical context.

Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.

Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT.

BACKGROUND: The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS). OBJECTIVES: The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs. DESIGN: Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis. SETTING: One hundred and twenty-five UK paediatric departments. PARTICIPANTS: Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years). INTERVENTIONS: The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1-4, 40 mg/m2 of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1-4; started at 60 mg/m2 of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m2 every 2 weeks (total 3150 mg/m2). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse [Albustix® (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months. RESULTS: There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank p = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p = 0.7), SDNS (44% vs. 42%; p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%; p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696). LIMITATIONS: Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating. CONCLUSIONS: This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit. FUTURE WORK: Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common childhood kidney diseases. The kidney filters leak protein into the urine, resulting in low levels of protein in the blood and generalised swelling. If untreated, this can lead to serious complications, including infection and blood clots. The disease responds well to prednisolone, a steroid drug; however, it is very common for disease to recur (called a relapse). Doctors are uncertain how long prednisolone should be given to treat children when they first present with nephrotic syndrome. In the UK, a 2-month course has traditionally been used. However, a number of research studies have suggested that giving prednisolone for ≥ 3 months may reduce the number of children who relapse and also the number who develop lots of relapses (called frequently relapsing nephrotic syndrome; FRNS). We recruited 237 children presenting with SSNS. Half were given an 8-week standard course of prednisolone and the other half a 16-week extended course (EC). We used placebo (dummy tablets) so that the participants and doctors did not know which treatment group they were in. Participants were followed for a minimum of 24 months and monitored for the development of relapses and prednisolone side effects, including behavioural problems. A cost analysis was performed. Giving EC prednisolone did not delay the development of disease relapse. There was also no difference in the number of children who developed FRNS or steroid-dependent nephrotic syndrome or who needed to be given other treatments. The rate of prednisolone side effects was the similar in the two treatment groups. EC treatment was, however, cheaper by £1673. Therefore, we conclude that there is no clinical benefit associated with the administration of EC prednisolone therapy in UK children presenting for the first time with SSNS. However, EC therapy was cheaper than the standard treatment.

Long-term outcome of paediatric renal transplantation: follow-up of 300 children from 1973 to 2000.

BACKGROUND/AIM: To report our experience of paediatric renal transplantation at Great Ormond Street and Royal Free Hospitals since the inception of the programme. METHODS: Retrospective review of the patient and transplant survival and influencing factors in the 300 children transplanted between 1973 and 2000. RESULTS: 300 children had received a total of 354 transplants; 56 were living-related donations. The median age at transplantation was 10.3 (range 1.4-17.9) years. Forty-four percent had congenital structural abnormalities of the urinary tract. Forty-six children required a second and 8 a third transplant before transfer to an adult unit. The overall patient survival at 5, 10, and 20 years was 97, 94, and 72%, respectively. In the overall cohort, the donor type (deceased donor or living-related donor) did not affect mortality, nor did age at transplantation, but those transplanted before 5 years of age had a significantly shorter post-transplant survival time (p < 0.0001). Transplant survival (first transplant) for deceased and living-related donors was 66 and 87% at 5 years (p < 0.01), 51 and 54% at 10 years, and 36% at 20 years (deceased-donor transplants only). Although the overall transplant survival was inferior in children transplanted before 2 years of age (p < 0.03), in the most recent cohort (1990-2000), age did not affect the outcome. On multiple regression analysis, the only predictor of transplant survival was the era of transplantation (p < 0.001). The median final height was within the normal range for males and females; 7 patients received growth hormone after transplantation. CONCLUSIONS: The outlook for successful transplantation is improving, and in the last decade was unaffected by age at transplantation. The survival of living-related donor transplants is superior to deceased-donor transplants for the first 5 years. From the above data, we can predict that a 10-year-old child receiving a renal transplant in 2000 and on ciclosporin-based immunosuppression can expect a transplant half-life of 13.1 years from a living-related donor and one of 10.8 years from a deceased-donor transplant.

Pediatric Deceased Donation-A Report of the Transplantation Society Meeting in Geneva.

The Ethics Committee of The Transplantation Society convened a meeting on pediatric deceased donation of organs in Geneva, Switzerland, on March 21 to 22, 2014. Thirty-four participants from Africa, Asia, the Middle East, Oceania, Europe, and North and South America explored the practical and ethical issues pertaining to pediatric deceased donation and developed recommendations for policy and practice. Their expertise was inclusive of pediatric intensive care, internal medicine, and surgery, nursing, ethics, organ donation and procurement, psychology, law, and sociology. The report of the meeting advocates the routine provision of opportunities for deceased donation by pediatric patients and conveys an international call for the development of evidence-based resources needed to inform provision of best practice care in deceased donation for neonates and children.

Glomerular tip changes in childhood minimal change nephropathy.

Segmental glomerular lesions at the tubular opening, or tip changes, are found in the renal biopsies of adults in many disorders, including some initially considered to show minimal change nephropathy. The hypothesis was that similar tip changes occurred in children. We reviewed a consecutive series of 50 biopsies, diagnosed as minimal change nephropathy, from 49 children. Segmental lesions were found in five biopsies. One biopsy showed lesions at the glomerular hilum. The patient was in remission at follow-up. Four biopsies showed only tip changes. Three patients were in remission, two on no treatment at follow-up, and one on ciclosporin. The other had chronic hepatitis B infection, with persistent proteinuria and segmental lesions at different sites in glomeruli. The other 44 children were nearly all in remission, 18 without treatment at follow-up, and the rest on various immunosuppressants, but one had persistent proteinuria and multiple segmental lesions. Series of childhood minimal change nephropathy, similar to this one, are likely to include cases of the glomerular tip lesion, under the original definition of minimal change nephropathy plus tip changes. This should make little difference in clinical practice, because the clinical course should resemble that of minimal change nephropathy.

Adrenocortical suppression increases the risk of relapse in nephrotic syndrome.

OBJECTIVE: Children with nephrotic syndrome (NS) are usually treated with long-term low dose alternate day prednisolone with or without glucocorticoid sparing therapy, such as levamisole or ciclosporin, to maintain remission. The degree of hypothalamic-pituitary-adrenal axis (HPA) suppression with such therapeutic strategies has not been studied systematically. HPA suppression could cause a relapse or adrenal crisis. STUDY DESIGN: To study the risks of HPA suppression, a modified low dose synacthen test (0.5 mug) was administered to 32 patients (22 male,10 female) with a mean age of 9.7 years (range 3.8-17.6 years) with NS receiving long-term alternate day prednisolone for over 12 months. Twelve patients received alternate day prednisolone, 11 alternate prednisolone+levamisole and nine alternate prednisolone+ciclosporin. All patients were followed up for 3 years and the relapse rate noted. RESULTS: 20/32 (62.5%) patients had a peak serum cortisol concentration of <500 nmol/l, which suggested suboptimal cortisol secretion and possible HPA suppression. 10/12 children in the prednisolone group and 8/11 in the levamisole group had a suboptimal cortisol response compared with 2/9 in the ciclosporin group. During follow-up, the 20 children who had a suboptimal cortisol response had significantly more relapses (95 relapses) compared to the 12 children with a normal cortisol response who had 24 relapses (p = 0.01). CONCLUSIONS: Children with NS receiving long-term alternate day prednisolone therapy are at risk of developing HPA suppression and should be evaluated using the modified synacthen test. Children with evidence of HPA suppression are at a greater risk of relapse.

Predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis.

Clinical and histological data of children presenting with steroid-resistant nephrotic syndrome and renal biopsy showing focal and segmental glomerulosclerosis from 1980 with a follow-up of over 10 years were reviewed. There were 66 patients; 38 male and 28 female. Age at onset ranged from 0.4-14.1 years (mean 6.4). Tubular atrophy was present at first biopsy in 50/66, capsular adhesions in 35/66, glomerular tip lesions in 8/66 and mesangial expansion in 31/66 patients. In 51 children, cyclophosphamide was prescribed as the first cytotoxic agent, while 15 received cyclosporine A and complete remission was induced in 43 and 40% of the children, respectively. Complete and stable remission was maintained in 35 children, while 22 had reduction of proteinuria with symptomatic relief. Nine were refractory to cytotoxic therapy. Of the 35 patients who entered complete and stable remission, the renal survival was over 90%, while in the 31 non-responders it was 48% in 10 years. The multivariate analysis using unconditional logistic regression method identified the presence of mesangial expansion (p=0.011) and tip lesions (p=0.005) as the independent predictors of favourable response to cytotoxic therapy and the presence of renal impairment (p=0.008) and extensive focal segmental sclerosis (p=0.025) as independent predictors of unfavourable response.

Correlation between finger-prick and venous ciclosporin levels: association with gingival overgrowth and hypertrichosis.

The aims of this study were (1) to ascertain ciclosporin C(2) 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 (C(2)). Seventy-two children (39 with SSNS, 33 with RT) participated. Ciclosporin 12 h trough (C(12)) and C(2) 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) C(2) levels in the SSNS and RT groups were 512 (+/-181) microg/l and 471 (+/-229) microg/l. There was a highly significant relationship between venous and finger-prick ciclosporin levels (r(2) = 0.96, P < 0.0001). Fourteen children had severe GO. There was a small, though statistically significant, impact of ciclosporin level on GO (C(2) r(2) = 0.12, P = 0.003 and C(12) r(2) = 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.

Steroid preservation: the rationale for continued prescribing.

Tailored immunosuppression according to risk stratification for optimal outcome for both immunological and non-immunological risk factors should be the ultimate objective for every child in whom renal transplantation is planned. Renal allograft survival is dependent on the appropriate use of immunosuppressive therapy to prevent acute rejection and chronic allograft nephropathy. Unfortunately, all immunosuppressive therapies, including corticosteroids, have unwanted side effects, including infections, malignancy, nephrotoxicity, hypertension, hyperlipidaemia and diabetes mellitus. However, the most worrying side effects of corticosteroids for children, adolescents and their parents are growth retardation and the cosmetic effects. Consequently, achieving immunosuppressive regimens without corticosteroids would be preferable. The major concern for paediatric nephrologists in the 21st century is no longer acute rejection, as the incidence appears to be decreasing, but infection, particularly EBV and the development of post-transplant lymphoproliferative disease (PTLD). With modern immunosuppressive agents in transplantation, rejection is being traded for infection. The long-term outcome data of PTLD with steroid-free and monoclonal antibody protocols is as yet unknown.

Childhood thin GBM disease: review of 22 children with family studies and long-term follow-up.

Thin glomerular basement membrane (GBM) disease is generally known to have a good renal prognosis, although renal insufficiency has sometimes been reported and the overlap with Alport syndrome implies that a good prognosis cannot be guaranteed. In order to shed light on long-term prognosis of thin GBM disease we have retrospectively evaluated 22 children with persistent haematuria and biopsy-proven thin GBM. Mean follow up was 7 years (range 2-17 years), mean age at onset was 7 years (range 1.5-15). Biopsies were performed a mean of 3.8 years after detection of hematuria. The light microscopy (LM) and immunofluorescence (IF) findings were essentially unremarkable in all of the children, while electron microscopy (EM) showed thinning of the GBM in all cases and no changes characteristic of Alport syndrome. The family history was positive for renal disease in 17 (77.3%) patients with hematuria in 8 (36.3%) families, and hematuria with renal failure (RF) or deafness in 9 (40.9%). It was completely negative for renal disease in 4 (18.2%) and unavailable in 1 (4.5%). Four patients (18%) showed a decline in renal function after 6, 8, 9 and 12 years of follow-up, and 1 of these also developed hearing impairment. None developed hypertension. Our study suggests that thin GBM disease is not always benign and a child with thin GBM should never be assigned such a prognosis, especially if there is a family history of renal impairment or deafness, where careful follow-up is needed due to the risk of late onset renal failure.

What is the calcineurin inhibitor of choice for pediatric renal transplantation?

Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.

Oral health in children with chronic renal failure.

Seventy children with chronic renal failure (CRF) aged 4-13.6 years were recruited from the Renal Unit of the Great Ormond Street Hospital for Children. Indices were recorded for dental caries, dental plaque, gingival inflammation, gingival enlargement, and enamel defects. Salivary urea, buffering capacity, and the oral streptococcal flora were determined for 25 of the children. A significantly greater proportion of the CRF children was caries free, 40% compared with 8.5% of the controls. The mean plaque score was significantly greater in the CRF group for both the primary 12.7 (16) and permanent dentition 22.0 (18.2) compared with the controls, 5.3 (7.6) and 15.5 (13.3), respectively. Eight CRF children had gingival enlargement. Enamel defects affecting the permanent teeth were observed in 57% of the CRF children compared with 33% of the controls. The buffering capacity was significantly greater in the CRF group, pH 6.4 (0.5) compared with the controls pH 5.6 (0.8). The mean salivary urea level (mmol/l) was significantly greater in the CRF children, 11.6 (5.9) compared with 3.6 (1.4) for the controls. The isolation frequency of Streptococcus mutans was significantly greater from controls compared with the CRF children ( P=0.002). An integrated dental service needs to be developed with emphasis on tooth brushing to prevent gingival hyperplasia and periodontal disease after puberty.

Gastrostomy feeding in infants and children on peritoneal dialysis.

The majority of infants and young children on peritoneal dialysis (PD) require enteral feeding to achieve their growth potential. We report our experience of gastrostomy feeding in 29 children on PD over 11 years. Fifteen children, median age 3.9 (0.5-13.3) years had a percutaneous gastrostomy (PEG) or Nissen fundoplication and gastrostomy (N and G) or open gastrostomy (OG) before starting PD (group1). Nine children, age 0.7 (0.5-12.4) years, had a N and G or OG (group 2) and 5, age 5.1 (1-15.1) years, a PEG (group 3) after PD catheter insertion/start of PD. In group 1 (257 months gastrostomy feeding with PD), there were 0.6 episodes of peritonitis/patient year. Nine PEGs were replaced electively after 27 (19-50) months, with bleeding from an embedded flange the only complication. One PEG replaced by a button ruptured the track, causing Candida peritonitis. In group 2 (130 months G and PD), there were 1.4 episodes of peritonitis/patient year. Two children developed paraoesophageal hernias, which were successfully repaired. Four children in group 3 developed peritonitis soon after PEG placement. Two transferred to haemodialysis, 1 remained on PD after treatment of Candida peritonitis and 1 subsequently died. Only 2 of the 17 children who have had renal transplants still need gastrostomy feeds. We recommend placement of a PEG or OG if an anti-reflux procedure is necessary prior to starting PD. Placement of a PEG while on PD is contraindicated, but an OG is a safe alternative procedure.