Carol Inward

Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome

Abstract. Autopsy material was examined from British children dying early in the course of haemolytic uraemic syndrome (HUS). These presented after 1983, the period in which verocytotoxin-producing Escherichia coli (VTEC) infection was confirmed as the leading cause of diarrhoea-associated (D+HUS) in the United Kingdom. Of 18 cases referred for this study, 3 were found on review to have no history of a diarrhoeal prodrome (D-HUS). In the D+ patients, the median duration from onset of diarrhoea to death was 8 days (range 4–42 days). VTEC infection was confirmed in 6 cases. All had neutrophilia at presentation (median 21, range 15–49.8 × 109/l). The 15 cases had uniform pathological features, consisting of glomerular thromboses and congested rather than ischaemic glomeruli. Arteriolar thromboses were common at the hilum of glomeruli and were sometimes also seen proximally, including in interlobular arteries. There were cortical infarcts in 5 cases with extensive thrombosis. Cases were demonstrated to have significantly greater numbers of neutrophils expressed per 100 glomeruli than controls, when counted using immunohistological stains to neutrophil elastase and CD15. This study showed uniformity of the renal changes in D+ HUS and gave further evidence of the importance of neutrophils in the pathogenesis of the disease.

Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period

End-stage renal disease requiring renal replacement therapy (RRT) during the neonatal period is a very rare condition, and little information is available regarding long-term RRT and outcomes. To gain more information, we performed a collaborative study on patient characteristics and treatment outcomes in children who started RRT as neonates during their first month of life between 2000 and 2011 who were prospectively registered in the ESPN/ERA-EDTA, the IPPN (since 2007), the Japanese registry, or the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry. During the first month of life, 264 patients from 32 countries started RRT and were followed for a median of 29 months (interquartile range 11-60 months). Most neonates (242) started on peritoneal dialysis, 21 started on hemodialysis, and 1 patient with a transplant. The most important causes of renal failure were congenital anomalies of the kidney and urinary tract in 141, cystic kidneys in 35, and cortical necrosis in 30. Within 2 years after the start of RRT, 69 children changed dialysis modality and 53 received a renal transplant. After a median of 7 months, 45 children had died, mainly because of infection, resulting in an estimated 2-year survival of 81%, and 5-year survival of 76%. Growth retardation (63%), anemia (55%), and hypertension (57%) were still major problems after 2 years. Thus, relatively good medium-term patient survival may be achieved with RRT started during the neonatal period, but specific therapeutic challenges continue to exist in this age group.

A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations, polymorphisms, and copy number variation in complement factors and inhibitors are associated with aHUS. In this study, we report the first functional non-synonymous polymorphism in the complement inhibitor C4b-binding protein (C4BP) alpha-chain (c.719G>A; p.Arg240His), which is associated with aHUS. This heterozygous change was found in 6/166 aHUS patients compared with 5/542 normal (chi2 = 6.021; p = 0.014), which was replicated in a second cohort of aHUS patients in which we found 5/170 carriers. The polymorphism does not decrease expression efficiency of C4BP. p.Arg240His is equally efficient as the wild type in binding and supporting degradation of C4BP but its ability to bind C3b and act as cofactor to its degradation both in fluid phase and on surfaces is impaired. This observation supports the hypothesis that dysregulation of the alternative pathway of complement is pivotal for aHUS. Three of the patients carry also mutations in membrane cofactor protein and factor H strengthening the hypothesis that individuals may carry multiple susceptibility factors with an additive effect on the risk of developing aHUS.

Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence

Of children with idiopathic nephrotic syndrome, 10%-20% fail to respond to steroids or develop secondary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation. Although 30%-50% of these patients suffer disease recurrence after transplantation, with poor long-term outcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrence after transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due to monogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consistently predict outcome of SRNS after transplantation. In all, 25 children had genetic or familial SRNS and did not experience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity, donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients, 57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity recurred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (odds ratio, 30; 95% confidence interval, 6.62 to 135.86; P<0.001). We were unable to determine recurrence in two patients (one with initial steroid sensitivity), and nine patients did not receive initial steroids. Our data show that initial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patient population. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be confirmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence.

The use of porcine dermal collagen implants in assisting abdominal wall closure of pediatric renal transplant recipients with donor size discrepancy

Abstract:  Children may have kidneys transplanted from donors larger than themselves. Abdominal wall closure may be difficult, with risks of abdominal compartment syndrome and graft compromise. Meshes used to facilitate closure may cause dense intra‐abdominal adhesions, making further surgery or peritoneal dialysis difficult. We present five cases in which abdominal wall closure was facilitated by porcine dermal collagen implant. Five children (2–15 yr) received transplanted kidneys from adult donors of significantly greater weight. In four recipients, the kidney was transplanted onto the aorta and vena cava intra‐abdominally using a midline incision. In the fifth, the kidney was anastomosed onto the iliac vessels. The skin overlying the implant was closed normally. Maximum follow‐up was three yr. In all cases, primary closure was achieved. One child received a second intra‐abdominal transplant as an emergency, which later failed. The other kidneys are functioning well. One recipient developed a small incisional hernia three yr post‐transplant. Another developed a skin dehiscence over the implant 23 days post‐operatively. The implant was removed and skin closed. The other two recipients recovered well. Porcine dermal collagen implant is a helpful adjunct to abdominal wall closure following organ transplantation in children with donor size discrepancy.

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype

Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.

UK Renal Registry 15th annual report: Chapter 4 demography of the UK paediatric renal replacement therapy population in 2011.

Aims: To describe the demographics of the paediatric RRT population under the age of 16 years in the UK and to analyse changes in demography with time. Methods: Data were collected from all 13 paediatric renal centres within the UK. A series of cross-sectional and longitudinal analyses were performed to describe the demographics of paediatric RRT patients. Results: A total of 856 children and young people under 18 with ERF were receiving treatment at paediatric nephrology centres in 2011. At the census date, 80.1% had a functioning transplant, 10.5% were receiving peritoneal dialysis (PD) and 9.4% were receiving haemodialysis (HD). In patients aged <16 years the prevalence of ERF was 56.8 pmarp and the incidence 8.3 pmarp. Analysis of trends over the last 15 years shows that both incidence and prevalence are increasing. A third of the prevalent patients had one or more reported comorbidities. At transfer to adult services, 86% of patients had a functioning renal transplant. Pre-emptive transplantation was seen to occur in 31% of children starting RRT under 16 years, with lower rates seen in girls and ethnic minorities. Survival in childhood amongst children starting RRT was the lowest in those aged less than 2 years. Conclusions: The data provided in this report show increasing trends over 15 years in the incidence and prevalence of established renal failure. This is important for the planning of the provision of care for children needing renal replacement therapy. Further research is required to understand the gender and ethnic differences in pre-emptive transplantation rates and the reduced survival amongst children aged less than 2 years.

UK Renal Registry 11th Annual Report (December 2008): Chapter 13 Demography of the UK paediatric renal replacement therapy population.

Aims: To describe the demographics of the paediatric RRT population in the UK and analyse changes in demographics with time. Methods: Extraction and analysis of data from the UK paediatric Renal Registry. Results: The UK paediatric established renal failure (ERF) population in April 2008 was 875 patients. The prevalence under the age of 16 years was 55 per million age related population (pmp) and the incidence 7.92 pmp. The incidence and prevalence for South Asian and Other ethnic groups were 3 times that of the White and Black populations. Renal dysplasia was the most common cause of ERF accounting for 33% of prevalent cases. Diseases with autosomal recessive inheritance were more common in patients from ethnic minority groups. The spectrum of diseases seen has changed over a generation. Overall 5 year survival for children with ERF was 91.8%. Five year survival of infants starting dialysis was just 62%. Transplanted patients accounted for 74% of the current population. The proportion with grafts from living donors has steadily risen to 34%. Children from ethnic minority groups were less likely to have an allograft and living donation was less frequent in this population. For those on dialysis, 57% were receiving peritoneal dialysis. This was the main treatment modality for patients under 4 years of age. Conclusions: The paediatric ERF population continued to expand slowly. Incidence and prevalence rates were stable and similar to other developed nations. The high incidence in patients from ethnic minority groups will lead to a greater proportion of the population being from these groups in time. To maintain the high proportion of engrafted patients it will be necessary to encourage living donation in the ethnic minority population. The spectrum of diseases seen has already changed over a generation with the treatment of young children with diseases such as congenital nephrosis. The incidence of cystinosis causing ERF was reduced, probably reflecting better early treatment.

UK Renal Registry 14th Annual Report

Aims: To describe the demographics of the paediatric RRT population under the age of 16 years in the UK and to analyse changes in demography with time. Methods: Data were collected from all 13 paediatric renal centres within the UK. A series of cross-sectional and longitudinal analyses were performed to describe the demographics of prevalent paediatric RRT patients. Results: A total of 870 children and young people under 18 with ERF were receiving treatment at paediatric nephrology centres in 2010. At the census date, 76.7% had a functioning transplant, 14.3% were receiving peritoneal dialysis (PD) and 9.0% were receiving haemodialysis (HD). In patients aged <16 years the prevalence of ERF was 59.3 pmarp and the incidence 8.1 pmarp. Analysis of trends over the last 15 years shows that both incidence and prevalence are increasing with the most marked increases in children aged 12–16 years and in ethnic minority groups. A third of the patients have one or more reported comorbidities. At transfer to adult services, 84.9% of patients had a functioning renal transplant. Conclusions: The data provided in this report show increasing trends over 15 years in the incidence and prevalence of established renal failure. This is important for the planning of the provision of care for children needing renal replacement therapy. The inclusion this year of an analysis of the patients transferring to adult services may assist in developing care pathways for this vulnerable group.

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Steroid-resistant nephrotic syndrome (SRNS), a heterogeneous disorder of the renal glomerular filtration barrier, results in impairment of glomerular permselectivity. Inheritance of genetic SRNS may be autosomal dominant or recessive, with a subset of autosomal recessive SRNS presenting as congenital nephrotic syndrome (CNS). Mutations in 53 genes are associated with human SRNS, but these mutations explain ≤30% of patients with hereditary cases and only 20% of patients with sporadic cases. The proteins encoded by these genes are expressed in podocytes, and malfunction of these proteins leads to a universal end point of podocyte injury, glomerular filtration barrier disruption, and SRNS. Here, we identified novel disease-causing mutations in membrane-associated guanylate kinase, WW, and PDZ domain-containing 2 (MAGI2) through whole-exome sequencing of a deeply phenotyped cohort of patients with congenital, childhood-onset SRNS. Although MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics, MAGI2 mutations have not been described in human SRNS. We detected two unique frameshift mutations and one duplication in three patients (two families); two siblings shared the same homozygous frameshift mutation, whereas one individual with sporadic SRNS exhibited compound heterozygosity. Two mutations were predicted to introduce premature stop codons, and one was predicted to result in read through of the normal translational termination codon. Immunohistochemistry in kidney sections from these patients revealed that mutations resulted in lack of or diminished podocyte MAGI2 expression. Our data support the finding that mutations in the MAGI2 gene are causal for congenital SRNS.