Alexander Hamilton

HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype–phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.

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 18th Annual Report: Chapter 10 Clinical, Haematological and Biochemical Parameters in Patients Receiving Renal Replacement Therapy in Paediatric Centres in the UK in 2014: National and Centre-specific Analyses

Introduction: The British Association for Paediatric Nephrology Registry (BAPN) was established to analyse data related to renal replacement therapy (RRT) in children. The registry receives data from the 13 paediatric nephrology centres in the UK. This chapter aims to provide centre specific data so that individual centres can reflect on the contribution that their data makes to the national picture and to determine the extent to which their patient parameters meet nationally agreed audit standards for the management of children with established renal failure (ERF). Methods: Data returns included a mixture of electronic (92%) and paper (8%) returns. Data were analysed to calculate summary statistics and where applicable the percentage achieving an audit standard. The standards used were those set out by the Renal Association and the National Institute for Health and Clinical Excellence. Results: Anthropometric data confirmed that children receiving RRT were short compared to healthy peers. Amongst patients with a height of <2SD between 2001 and 2012, 29.2%were receiving growth hormone if they were on dialysis compared to 11.9% if they had a functioning transplant. Prevalence rates of overweight and obese status in children with ERF remain concerningly high. Blood pressure control remained challenging with wide inter-centre variation although this was significantly better in children with a functioning transplant. Over a quarter of haemodialysis patients and 17.3% of peritoneal dialysis patients were anaemic, compared to only 8.3% of transplanted patients. ESA use in the dialysis population exceeded 90% amongst anaemic patients. The control of renal bone disease remained challenging. Conclusions: Optimising growth and reducing prevalent excess weight in children on RRT remains challenging. The likelihood of complete electronic reporting in the near future with plans for quarterly reporting in the format of the recently finalised NEW paediatric dataset will hopefully improve quality of data and their reporting, allowing improvements in patient care.

Impact of Month of Birth on the Development of Autoimmune Thyroid Disease in the United Kingdom and Europe

CONTEXTnViral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves disease (GD) and Hashimotos thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life.nnnOBJECTIVEnMonth of birth effects were investigated in three independent European Caucasian AITD datasets.nnnDESIGNnVariation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test.nnnSETTINGnThe study was conducted at a research laboratory.nnnPATIENTSnNational UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent).nnnMAIN OUTCOME MEASURESnCase-control and family-based association studies were measured.nnnRESULTSnNo consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walters test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort.nnnCONCLUSIONnOur results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphism and Left Ventricular Function in Early Chronic Kidney Disease

Background Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated. Methods 140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively. Results The median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively). Conclusions eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.

UK Renal Registry 18th Annual Report: Chapter 4 Demography of Patients Receiving Renal Replacement Therapy in Paediatric Centres in the UK in 2014

A total of 917 children and young people under 18 years with established renal failure (ERF) were receiving treatment at paediatric nephrology centres in 2014.At the census date (31st December 2014), 79.3% of prevalent paediatric patients aged ,18 years had a functioning kidney transplant, 11.2% were receiving haemodialysis (HD) and 9.5% were receiving peritoneal dialysis (PD). In patients aged ,16 years, prevalence of ERF was 60.4 per million age related population (pmarp) and the incidence 9.4 pmarp. The most common primary renal diagnosis was renal dysplasia+reflux, present in 32.6% of prevalent paediatric patients aged ,16 years. About a third of patients had one or more reported comorbidity at onset of renal replacement therapy (RRT). The improvement in rates of pre-emptive transplantation for those referred early has been maintained over the last 10 years at 37.5%, compared to 27.4% in 2000–2004. At transfer to adult services, 90.3% of patients had a functioning kidney transplant. Survival during childhood amongst children commencing RRT was the lowest in those aged less than two years compared to those aged 12 to less than 16 years with a hazard ratio of 4.1 (confidence interval 2.2–8.0), and in those receiving dialysis compared to having a functioning transplant with a hazard ratio of 6.3 (confidence interval 3.9–10.2).

Irreversible renal damage from accidental mushroom poisoning

Nicholas Evans, author of The Horse Whisperer, tells the story of his journey through acute renal failure to successful transplantation.

Autoimmune haemolytic anaemia associated with Epstein Barr virus infection as a severe late complication after kidney transplantation and successful treatment with rituximab: case report.

BackgroundAutoimmune haemolytic anaemia (AIHA) is a rare complication following kidney transplantation and usually occurs early in its course. It is characterised by autoantibodies or alloantibodies directed against red blood cells (RBCs).Case presentationWe describe a 44xa0year old woman who presented 5xa0years after kidney transplantation with profound transfusion dependent warm AIHA. Investigations confirmed an IgG autoantibody against RBCs and high titre Epstein-Barr virus (EBV) viraemia. The patient was at higher risk for EBV disease being seronegative at the time of transplantation but had detectable EBV capsid IgG antibody at the time of presentation. The haemolysis was refractory to high dose steroid and intravenous immunoglobulin. There was a rapid and complete resolution of both the anaemia and the viraemia following rituximab therapy, with no adverse events. Twenty-six units of blood were required during the course of treatment.ConclusionsTo our knowledge this is the first reported case of EBV associated AIHA in a renal transplant recipient. It highlights a rare pathology associated with post-transplant EBV infection, of broad interest to transplant physicians, haematologists, and microbiologists, and the effective novel use of monoclonal anti-CD20 therapy.

Systemic pANCA-associated vasculitis with central nervous involvement causing recurrent myelitis: case report

BackgroundWe report on the case of an established perinuclear antineutrophil cytoplasmic antibody (pANCA) associated renal vasculitis being treated with prednisolone and rituximab, where the patient presented with leg weakness, urinary and faecal incontinence and buttock pain consistent with transverse myelitis.Case presentationThe patient underwent MRI scanning showing patchy cord enhancement from T10 to the conus, which was suggestive of a cord malignancy. Prior to a cord biopsy, he was treated with steroids and a repeat MRI showed resolution of the original lesion with a new similar lesion from C7 to T3.ConclusionsHe made a marked recovery after further treatment with high dose steroids and plasma exchange.

The clinical epidemiology of young adults starting renal replacement therapy in the UK: presentation, management and survival using 15 years of UK Renal Registry data

Abstract Background Clinical epidemiology data for young adults on renal replacement therapy (RRT) are lacking. While mostly transplanted, they have an increased risk of graft loss during young adulthood. Methods We combined the UK Renal Registry paediatric and adult databases to describe patient characteristics, transplantation and survival for young adults. We grouped patients 11–30 years of age starting RRT from 1999 to 2008 by age band and examined their course during 5 years of follow-up. Results The cohort (nu2009=u20093370) was 58% male, 79% white and 29% had glomerulonephritis. Half (52%) started RRT on haemodialysis (HD). Most (78%) were transplanted (18% pre-emptive, 61% as second modality); 11% were not listed for transplant. Transplant timing varied by age group. The deceased:living donor kidney transplant ratio was 2:1 for 11–<16 year olds and 1:1 otherwise. Median deceased donor transplant waiting times ranged from 6 months if <16 years of age to 17 months if ≥21 years. Overall 8% died, with being on dialysis and not transplant listed versus transplanted {hazard ratio [HR] 16.6 [95% confidence interval (CI) 10.8–25.4], Pu2009<u20090.0001} and diabetes versus glomerulonephritis [HR 4.03 (95% CI 2.71–6.01), Pu2009<u20090.0001] increasing mortality risk. Conclusions This study highlights the frequent use of HD and the importance of transplant listing and diabetes for young adults. More than half the young adults in our cohort started renal replacement therapy on HD. One in 10 young adults were not listed for transplant by 5 years and were ∼20 times more likely to die than those who were transplanted. Diabetes as a primary renal disease was common among young adults and associated with increased mortality. Overall, almost 1 in 10 young adults had died by 5 years from the start of RRT.