Kidney transplantation in low- and middle-income countries: the Transplant Links experience.

Paediatric kidney failure is a global problem responsible for significant childhood morbidity and mortality. The gold-standard treatment is kidney transplantation. However, the availability of kidney transplantation remains limited in some low- and middle-income countries (LMICs). Transplant Links Community (TLC) is a UK-based charity that mentors units in LMICs wishing to start kidney transplantation; the ultimate goal is for these units to become self-sufficient. TLC provides this support through in-person training visits and skill transfer, plus direct mentorship from the UK that is maintained over many years. From such mentoring programmes, it is evident that there are numerous challenges in the initial establishment and long-term maintenance of kidney transplant services, with specific and unique barriers applying to setting up paediatric transplant programmes compared to their adult counterparts. This review summarises TLC's first-hand experience of developing paediatric kidney transplantation services in LMICs over the past 15 years, the challenges encountered, and the major ongoing barriers that must be addressed to facilitate further progress in delivering transplantation services to children globally.

Kidney biopsy findings in children with diabetes mellitus.

BACKGROUND: Diabetic nephropathy may begin in childhood, but clinical kidney disease ascribable to this is uncommon in children with type 1 (insulin dependent) diabetes mellitus. METHODS: We reviewed our experience of kidney biopsies in children with type 1 diabetes mellitus. RESULTS: Between 1995 and 2022, there were biopsies in 17 children, with various clinical indications for kidney biopsy, making this the largest series of biopsies in diabetic children with clinical kidney abnormalities. Four biopsies showed diabetic nephropathy, three showed the combination of diabetic nephropathy and IgA nephropathy, and ten showed a variety of conditions other than diabetic nephropathy: minimal change disease (2), membranous nephropathy (2), thin glomerular basement membrane lesion (2), non-glomerular chronic damage in Wolcott-Rallison syndrome (2), acute pauciimmune necrotizing crescentic glomerulonephritis (1) and IgA nephropathy (1). Clinical clues of something other than diabetic nephropathy included acute kidney injury, microscopic haematuria or chronic kidney impairment with little or no proteinuria and the nephrotic syndrome after a short duration of diabetes. CONCLUSIONS: We confirm that changes better known in adults with either type 1 or type 2 diabetes mellitus can occur in children with type 1 diabetes mellitus: overt diabetic nephropathy either on its own or combined with other conditions and kidney disorders other than diabetic nephropathy.

Successful ABO and HLA incompatible kidney transplantation in children in the UK.

BACKGROUND: There is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK. METHODS: Questionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups. RESULTS: Among 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6-14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder. CONCLUSION: Longer term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible. A higher resolution version of the Graphical abstract is available as Supplementary information.

Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease.

BACKGROUND: Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk. METHODS: This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis. RESULTS: Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (ß = -0.43 , P < 0.0001), ALP (ß = -0.36, P < 0.0001) and Ca (ß = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model. CONCLUSIONS: Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Utility and safety of plasma exchange in paediatric neuroimmune disorders.

AIM: Our aim was to ascertain the indications, side effects, and outcomes in children receiving therapeutic plasma exchange (TPE) for neurological disorders. METHOD: Medical records were retrospectively reviewed for 58 consecutive children (age ≤16y) undergoing 67 courses of TPE across four tertiary centres. Patient characteristics, treatment schedules, complications, and outcomes were analysed. RESULTS: Median age at initiation of TPE was 9 years (range 1-15y). Indications included peripheral nervous system (PNS; n=18) and central nervous system (CNS; n=40) disorders. Courses comprised a median six exchanges (range 2-179) over 8 days (range 3-466). Forty-two out of 58 (73%) children were severely disabled (bedridden) at initiation and 24 out of 58 (41%) were admitted to intensive care units. Treating clinicians' impression of response was positive in 16 out of 18 of those with PNS disorders versus 22 out of 40 with CNS disorders (p=0.016). Improvements in disability (modified Rankin Scale) occurred in 13 out of 58 (22%) children by completion of TPE (p=0.003). Complications occurred in 40 out of 67 (60%) courses, of which 16 out of 67 (24%) were line related. Potentially life-threatening complications occurred in 2 out of 67 (3%) courses. INTERPRETATION: This cohort study provides safety and efficacy information for clinicians and families and a basis for future prospective studies. WHAT THIS PAPER ADDS: Disability scores for severe neuroimmune disorders remained stable or improved during therapeutic plasma exchange treatment. Complications occurred frequently but were typically mild and correctable.

UTILIDAD Y SEGURIDAD DEL INTERCAMBIO DE PLASMA EN TRASTORNOS NEUROINMUNES PEDIÁTRICOS: OBJETIVO: Nuestro objetivo fue determinar las indicaciones, los efectos secundarios y los resultados en niños que recibieron intercambio terapéutico de plasma (TPE) para trastornos neurológicos. MÉTODO: Se revisaron retrospectivamente los registros médicos de 58 niños consecutivos (≤16 años) que se sometieron a 67 cursos de TPE en cuatro centros terciarios. Se analizaron las características de los pacientes, los esquemas de tratamiento, las complicaciones y los resultados. RESULTADOS: La edad mediana al inicio de la TPE fue de 9 años (rango 1-15 años). Las indicaciones incluían trastornos del sistema nervioso periférico (SNP; n = 18) y del sistema nervioso central (SNC; n = 40). Los cursos comprendieron una mediana de 6 intercambios (rango 2-179) durante 8 días (rango 3-466). Cuarenta y dos de 58 (73%) niños presentaban un grado de discapacidad severa (postrados en cama) al inicio y 24 de 58 (41%) fueron ingresados en unidades de cuidados intensivos. El tratamiento de la impresión de respuesta de los médicos fue positivo en 16 de 18 de las personas con trastornos de SNP versus 22 de 40 en trastornos del SNC (p = 0,016). Las mejoras en la discapacidad (escala de Rankin modificada) se produjeron en 13 de los 58 (22%) niños al completar el TPE (p = 0,003). Las complicaciones ocurrieron en 40 de 67 cursos (60%), de los cuales 16 de 67 (24%) estaban relacionados con la línea. Complicaciones potencialmente peligrosas para la vida ocurrieron en 2 de 67 (3%) cursos. INTERPRETACIÓN: Este estudio de cohorte proporciona información de seguridad y eficacia para profesionales y familiares y una base para futuros estudios prospectivos.

UTILIDADE E SEGURANÇA DA TRANSFERÊNCIA DE PLASMA EM TRANSTORNOS NEUROIMUNES PEDIÁTRICOS: OBJETIVO: Nosso objetivo foi verificar as indicações, efeitos colaterais, e resultados em crianças recebendo transferência terapêutica de plasma (TTP) para transtornos neurológicos. MÉTODO: Registros médicos foram retrospectivamente revisados para 58 crianças (idade ≤16a) passando por 67 cursos de TTP em quatro centros terciários. Características dos pacientes, rotina de tratamento, complicações e resultados foram analisados. RESULTADOS: A idade mediana ao início da TTP foi 9 anos (variação 1-15 anos). Indicações incluíram transtornos do sistema nervoso periférico (SNP; n = 18) e sistema nervoso central (SNC; n = 40) disorders. Os cursos compreenderam uma mediana de seis transferências (variação 2-179) em 8 dias (variação 3-466). Quarenta e duas em 58 (73%) crianças estavam severamente incapacidadas (acamadas) no início e 24 em 58 (41%) foram admitidas em unidades de cuidado intensivo. A impressão de resposta dos clínicos que as tratavam foi positiva em 16 de 18 daquelas com transtornos do SNP versus 22 de 40 daquelas com desordens do SNC (p = 0,016). Melhoras na incapacidade (Escala de Rankin modificada) ocorreram em 13 de 58 (22%) crianças ao final da TTP (p = 0,003). Complicações ocorreram em 40 de 67 (60%) cursos, dos quais 16 em 67 (24%) eram relacionados à linha. Complicações com potencial risco de vida ocorreram em 2 de 67 (3%) cursos. INTERPRETAÇÃO: Este estudo de coorte fornece informação sobre a segurança e eficácia para clínicos e famílias, e uma base para futuros estudos prospectivos.

Proteinuric kidney disease in children at Queen Elizabeth Central Hospital, Malawi.

BACKGROUND: There is a paucity of data on paediatric kidney disease in developing countries such as Malawi. Descriptive research on kidney disease is essential to improving patient outcomes. METHODS: We conducted a cross-sectional study at a tertiary hospital in Malawi from 2012 to 2013. Children under 14 years with proteinuric kidney disease were enrolled from paediatric wards and outpatient clinics at Queen Elizabeth Central Hospital (QECH). Demographic, clinical and laboratory data were collected from patients at enrolment and at 3 months review at which point clinical status and disease outcome were ascertained. RESULTS: Thirty-four (22 male) patients were studied, mean age 8.54 (SD = 3.62 years). Glomerular disease (n = 25, 68%) was the most common presumed renal lesion at presentation. Nephritic syndrome (10) was characterised by a lower baseline complement C3 than nephrotic syndrome (p = 0.0027). Seven (47%) cases of nephrotic syndrome achieved complete remission. Eight (80%) cases of nephritic syndrome improved with supportive therapy. Nineteen (56%) patients presented with clinically significant renal damage with eGFR< 60 ml/min/1.73m2. Six patients presented in chronic kidney disease (CKD) stage 5 of unclear aetiology, five (83%) died. Three (9%) patients had impaired kidney function and obstructive uropathy demonstrated on ultrasound, two recovered after surgery and one died. Eight (24%) patients had acute kidney injury (AKI) due to primary kidney disease, three of these patients progressed to CKD stage G3a. Seven (21%) patients were lost to follow up. CONCLUSION: Kidney disease is a significant cause of mortality and morbidity in children at QECH. Less than half of Nephrotic syndrome cases achieved complete remission. Mortality is highest in children with CKD of unclear cause. Some patients with AKI secondary to primary renal disease progressed to CKD. Understanding the aetiology of paediatric kidney disease and improving patient outcomes by developing enhanced diagnostic and clinical services are priorities at QECH and within Malawi.

Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome.

Bardet-Biedl syndrome is a rare autosomal recessive, multisystem disease characterized by retinal dystrophy, renal malformation, obesity, intellectual disability, polydactyly, and hypogonadism. Nineteen disease-causing genes (BBS1-19) have been identified, of which mutations in BBS1 are most common in North America and Europe. A hallmark of the disease, renal malformation is heterogeneous and is a cause of morbidity and mortality through the development of CKD. We studied the prevalence and severity of CKD in 350 patients with Bardet-Biedl syndrome-related renal disease attending the United Kingdom national Bardet-Biedl syndrome clinics to further elucidate the phenotype and identify risk indicators of CKD. Overall, 31% of children and 42% of adults had CKD; 6% of children and 8% of adults had stage 4-5 CKD. In children, renal disease was often detected within the first year of life. Analysis of the most commonly mutated disease-associated genes revealed that, compared with two truncating mutations, two missense mutations associated with less severe CKD in adults. Moreover, compared with mutations in BBS10, mutations in BBS1 associated with less severe CKD or lack of CKD in adults. Finally, 51% of patients with available ultrasounds had structural renal abnormalities, and 35% of adults were hypertensive. The presence of structural abnormalities or antihypertensive medication also correlated statistically with stage 3b-5 CKD. This study describes the largest reported cohort of patients with renal disease in Bardet-Biedl syndrome and identifies risk factors to be considered in genetic counseling.

Fatal disseminated cowpox virus infection in an adolescent renal transplant recipient.

BACKGROUND: A 17-year-old boy on long-term immunosuppression following renal transplantation for chronic kidney disease (CKD), the result of dysplastic kidneys, initially presented with a swelling in his neck while attending hospital for an unrelated problem. A clinical diagnosis of tonsillitis was made, and he was treated with broad-spectrum antibiotics. Over a few days, his condition deteriorated, and he developed multiple vesicopustular skin lesions and required an emergency tonsillectomy due to respiratory distress. CASE DIAGNOSIS/TREATMENT: Histological investigation of the skin and tonsillar tissue suggested a viral aetiology, and subsequent electron microscopy and polymerase chain reaction (PCR) tissue examination proved disseminated cowpox infection. The family cat, which was reported as having self-resolving sores on its skin, was likely the source of the infection. The child failed to respond to antiviral treatment and succumbed to multiorgan failure within a month of admission. CONCLUSIONS: We report this case of fatal disseminated cowpox infection to highlight an increasing risk of this illness in the post-transplant population and to detail some unusual features not previously described, such as tonsillar involvement, disseminated skin lesions and multiorgan failure.

Combined liver and kidney transplantation in children: analysis of renal graft outcome.

BACKGROUND: Combined liver-kidney transplantation (CLKT) is the accepted treatment for patients with both liver failure and progressive renal insufficiency. Long-term outcome data for CLKT in children is sparse and controversy exists as to whether simultaneous CLKT with organs from the same donor confers immunologic and survival benefit to the kidney allograft. We report the long-term renal graft outcomes of 40 patients who had simultaneous CLKT. METHODS: A retrospective analysis of kidney graft survival (time from transplantation to death, return to dialysis or last follow-up event) in all pediatric patients (age < 18 years old) who underwent CLKT from March 1994 to January 2015. A 1:1 ratio of controls (deceased donor kidney recipients from our centre matched for age (±2 years) at transplant, time from transplant (±1 year) and treated with the same immunosuppressive regime) to cases was used to compare outcome. Estimated glomerular filtration rate (e-GFR) was calculated using the Schwartz formula. Survival curves were determined using Kaplan-Meier analysis. RESULTS: The kidney graft survival for CLKT patients was 87.4, 82, and 82 % at 1, 5, and 10 years; kidney graft survival for isolated KT patients were 97.2, 93, and 93 % at 1, 5, and 10 years (p = NS). There were two acute rejection episodes (5 %) in the CLKT group compared to five (12.5 %) episodes in the isolated KT group. There was no statistically significant difference in e-GFR at 1, 5, and 10 years in the two groups but there was a statistically significantly greater decline in e-GFR in the KT group compared to CLKT group from 5-10 years following transplant. CONCLUSIONS: There are fewer acute rejection episodes following CLKT compared to isolated KT, and we noted a higher mean e-GFR at 1, 5, and 10 years with significantly lesser decline in e-GFR from 5 to 10 years in the CLKT group.

Tolvaptan is successful in treating inappropriate antidiuretic hormone secretion in infants.

AIM: Using fluid restriction to treat the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in infants is potentially hazardous, as fluid intake and caloric intake are connected. Antagonists for the type 2 vasopressin receptor have demonstrated efficacy in adult patients with SIADH, but evidence in children is lacking. We reviewed our experience from two cases in the UK. METHODS: This was a retrospective review of the clinical data on two patients diagnosed with SIADH in infancy and treated with tolvaptan, an oral vasopressin receptor antagonist. RESULTS: Persistent hyponatraemia was noted in both patients in the first month of life and eventually led to SIADH diagnoses. Initial salt supplementation in one patient resulted in severe hypertension, treated with four antihypertensive drugs. Tolvaptan was commenced at two and four months of age, respectively, and was associated with normalisation of plasma sodium values and blood pressure without the need for antihypertensive treatment. There was transient hypernatraemia in one patient, which was normalised with a dose reduction. Tolvaptan was administered by crushing the tablet and mixing it with water. CONCLUSION: Tolvaptan provided effective treatment for SIADH in both infants and could be administered orally.

The definition of acute kidney injury and its use in practice.

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

Successful ABO incompatible renal transplantation following rituximab and DFPP after failed immunoadsorption.

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.

Soluble CD30 and ELISA-detected human leukocyte antigen antibodies for the prediction of acute rejection in pediatric renal transplant recipients.

Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well-controlled prospective randomized trial was analyzed pre- and post-transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T-cell reactivity, and anti-human leukocyte antigen (anti-HLA) antibody reactivity, a biomarker for B-cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy-proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut-off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut-off (P = 0.004). For pre- and post-transplant anti-HLA class II reactivities by enzyme-linked immunosorbent assay, a cut-off value of 140 optical density was able to discriminate rejecters from nonrejecters with a sensitivity of 86% or 71% and a specificity of 81% or 90%, respectively. Withdrawal of steroids was associated with a approximately twofold higher serum sCD30 compared to controls, but did not affect anti-HLA reactivities. An increased post-transplant sCD30 serum concentration and positive pre- and post-transplant anti-HLA class II reactivities are informative biomarkers for impending BPAR in pediatric renal transplant recipients. (TWIST, Clinical Trial No: FG-506-02-43).

Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series.

We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.

Phenotypic variation and long-term outcome in children with congenital hepatic fibrosis.

BACKGROUND AND OBJECTIVE: Congenital hepatic fibrosis (CHF) and Caroli syndrome are frequently associated with renal cystic diseases. They have a variable clinical course, and the natural history is not well defined despite molecular advances. Our study describes the clinical manifestations and long-term outcome in children with this disorder. METHODS: A retrospective case review of children with CHF at a single centre diagnosed on the basis of clinical features, radiological and endoscopic evidence of portal hypertension (PHT), and compatible histopathological findings. Children were categorised based on hepatic phenotype-group 1 (Caroli syndrome) and group 2 (CHF). Hepatobiliary as well as renal manifestations were recorded at presentation, and their evolution followed up until transplant or last follow-up. RESULTS: There were 40 children (22 boys) with a median age of 1.3 years at clinical presentation. Fourteen of 40 (35%) children presented in the neonatal period with primarily renal disease, of whom 11 (78%) had Caroli syndrome (P = 0.02). Significant PHT with oesophageal varices was seen in 86%, with no difference in the incidence of gastrointestinal bleeding and varices between Caroli syndrome and CHF. Cholangitis developed in 10 of 40 (25%) and was more common in the Caroli syndrome group (P = 0.009). A higher proportion of children with Caroli syndrome developed chronic kidney disease (CKD) stage 3 and above as compared with CHF (85% vs 42%; P = 0.007). Twelve of 21 (57%) and 8 of 19 (42%) children in the Caroli syndrome and CHF groups required either combined liver-kidney or isolated liver transplant, with the most common indication for renal transplantation being end-stage renal disease (CKD5d) with or without advanced PHT or cholangitis. All 14 (100%) children with neonatal presentation developed CKD5d and required combined liver-kidney transplant before 14 years of age, whereas 77% of children presenting beyond the neonatal period survived without liver-kidney transplant (P < 0.001). Neonatal presentation was the best predictor of the need for transplant. CONCLUSIONS: Caroli syndrome is more likely to present in the neonatal period and these patients are more likely to develop CKD5d. CKD stage 3 or above with recurrent cholangitis is more common in Caroli syndrome presenting beyond the neonatal period and adds to the significant morbidity in these patients. Children presenting in the neonatal period have a more severe phenotype and should be considered early for combined liver-kidney transplant.

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis.

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P = 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P = 0.09). Median cIMTz and PWVz showed nonsignificant increase (P = 0.23 and P = 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2 = 0.48, ß = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n = 24). Conclusion: This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features-outcome.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and systemic vasculitis (AAGNV) is uncommon in childhood. METHODS: This is a retrospective study of AAGNV cases diagnosed over a 13-year period in a tertiary pediatric nephrology department. RESULTS: Thirteen cases of AAGNV were identified: seven Wegener granulomatosis (WG) and six microscopic polyangiitis (MPA). Acute renal failure/nephrotic range proteinuria (NRP) was found in 77 % of the patients (4 with WG, all with MPA). Eleven (85 %) patients showed necrotizing glomerulonephritis (NGN), with ≥50 % crescents identified in nine patients (69 %) (4 with WG, 5 with MPA). Treatment with methylprednisolone, cyclophosphamide and plasma exchange resulted in extra-renal remission and antibody reduction in all patients and renal function improvement/stabilization in 77 % of the patients. Three patients, all without oliguria at presentation and few sclerotic lesions, had normal renal function at follow-up. Chronic kidney disease (CKD) stages 2 and 3-4 were observed in four (WG) and three (MPA) patients, respectively. Three patients (23 %) developed end stage renal disease: two were MPA patients with severe presentation (markedly impaired glomerular filtration rate, oliguria, NRP, crescentic NGN, glomerular sclerosis) and one was a WG patient with extensive interstitial fibrosis/tubular atrophy. CONCLUSIONS: Severe renal involvement was more common in children with MPA than WG. Treatment with methylprednisolone, cyclophosphamide and plasma exchange induced extra-renal remission/serological response and renal function improvement/stabilization. Markedly decreased GFR, oliguria, NRP, and chronic glomerular lesions at presentation were predictors of poor outcome.