The spectrum of co-existing disease in children with established kidney failure using registry and linked electronic health record data.

BACKGROUND: Children with established kidney failure may have additional medical conditions influencing kidney care and outcomes. This cross-sectional study aimed to examine the prevalence of co-existing diseases captured in the electronic hospital record compared to UK Renal Registry (UKRR) data and differences in coding. METHODS: The study population comprised children aged < 18 years receiving kidney replacement therapy (KRT) in England and Wales on 31/12/2016. Comorbidity data at KRT start was examined in the hospital record and compared to UKRR data. Agreement was assessed by the kappa statistic. Associations between patient and clinical factors and likelihood of coding were examined using multivariable logistic regression. RESULTS: A total of 869 children (62.5% male) had data linkage for inclusion. UKRR records generally reported a higher prevalence of co-existing disease than electronic health records; congenital, non-kidney disease was most commonly reported across both datasets. The highest sensitivity in the hospital record was seen for congenital heart disease (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.51, 0.78) and malignancy (OR 0.63, 95% CI 0.41, 0.85). At best, moderate agreement (kappa ≥ 0.41) was seen between the datasets. Factors associated with higher odds of coding in hospital records included age, while kidney disease and a higher number of comorbidities were associated with lower odds of coding. CONCLUSIONS: Health records generally under-reported co-existing disease compared to registry data with fair-moderate agreement between datasets. Electronic health records offer a non-selective overview of co-existing disease facilitating audit and research, but registry processes are still required to capture paediatric-specific variables pertinent to kidney disease.

Psychosocial Health and Lifestyle Behaviors in Young Adults Receiving Renal Replacement Therapy Compared to the General Population: Findings From the SPEAK Study.

RATIONALE & OBJECTIVE: Patients in late adolescence and early adulthood receiving renal replacement therapy (RRT) face disruption to normal activities, which affects well-being. We aimed to define psychosocial and lifestyle outcomes for young adults on RRT compared to the general population. STUDY DESIGN: We undertook a cross-sectional survey (the SPEAK [Surveying Patients Experiencing Young Adult Kidney Failure] Study) using validated measures and general population comparator data from the Health Survey for England and Avon Longitudinal Study of Parents and Children. Additional clinical information was obtained from the UK Renal Registry. SETTING & PARTICIPANTS: 16- to 30-year-olds receiving RRT. OUTCOMES: Psychosocial health and lifestyle behaviors. ANALYTICAL APPROACH: We compared outcomes between populations using age- and sex-adjusted regression models, weighted to account for response bias by sex, ethnicity, and socioeconomic status. Our findings were used to update recent meta-analyses. RESULTS: We recruited 976 young adults and 64% responded to the survey: 417 (71%) with kidney transplants and 173 (29%) on dialysis therapy. Compared to the general population, young adults on RRT were less likely to be in a relationship and have children and more likely to live in the family home, receive no income, and be unable to work due to health. They had poorer quality of life, worse well-being, and twice the likelihood of a psychological disturbance (OR, 2.7; 95% CI, 2.0-3.7; P<0.001). They reported less smoking, alcohol and drug abuse, and crime. In a meta-analysis, our study showed the greatest differences in quality of life compared to the general population. LIMITATIONS: Cross-sectional study design, meaning that we could not track the impact of treatment changes on the outcomes. CONCLUSIONS: This study involving a large cohort of young adult transplant recipients and dialysis patients provides evidence of worse psychosocial outcomes but more positive lifestyle behaviors in young adults on RRT compared to the age-matched general population.

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.

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 (n = 3370) 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], P < 0.0001} and diabetes versus glomerulonephritis [HR 4.03 (95% CI 2.71-6.01), P < 0.0001] 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.

Continually improving standards of care: The UK Renal Registry as a translational public health tool.

A disease registry uses observational study methods to collect defined data on patients with a particular condition for a predetermined purpose. By providing comprehensive standardised data on patients with kidney disease, renal registries aim to provide a 'real world' representation of practice patterns, treatment and patient outcomes that may not be captured accurately by other methods, including randomised controlled trials. Additionally, using registries to measure variations in outcomes and audit care against standards is crucial to understanding how to improve quality of care for patients in an efficacious and cost-effective manner. Registries also have the potential to be a powerful scientific tool that can monitor and support the translational process between research and routine clinical practice, although their limitations must be borne in mind. In this review, we describe the role of the UK Renal Registry as a tool to support translational research. We describe its involvement across each stage of the translational pathway: from hypothesis generation, study design and data collection, to reporting of long-term outcomes and quality improvement initiatives. Furthermore we explore how this role may bring about improvements in care for adults and children with kidney disease.

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.

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a ß 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.

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.

Epidemiology of childhood acute kidney injury in England using e-alerts.

Background: Few studies describe the epidemiology of childhood acute kidney injury (AKI) nationally. Laboratories in England are required to issue electronic (e-)alerts for AKI based on serum creatinine changes. This study describes a national cohort of children who received an AKI alert and their clinical course. Methods: A cross-section of AKI episodes from 2017 are described. Hospital record linkage enabled description of AKI-associated hospitalizations including length of stay (LOS) and critical care requirement. Risk associations with critical care (hospitalized cohort) and 30-day mortality (total cohort) were examined using multivariable logistic regression. Results: In 2017, 7788 children (52% male, median age 4.4 years, interquartile range 0.9-11.5 years) experienced 8927 AKI episodes; 8% occurred during birth admissions. Of 5582 children with hospitalized AKI, 25% required critical care. In children experiencing an AKI episode unrelated to their birth admission, Asian ethnicity, young (<1 year) or old (16-<18 years) age (reference 1-<5 years), and high peak AKI stage had higher odds of critical care. LOS was higher with peak AKI stage, irrespective of critical care admission. Overall, 30-day mortality rate was 3% (n = 251); youngest and oldest age groups, hospital-acquired AKI, higher peak stage and critical care requirement had higher odds of death. For children experiencing AKI alerts during their birth admission, no association was seen between higher peak AKI stage and critical care admission. Conclusions: Risk associations for adverse AKI outcomes differed among children according to AKI type and whether hospitalization was related to birth. Understanding the factors driving AKI development and progression may help inform interventions to minimize morbidity.

Associations between Deprivation, Geographic Location, and Access to Pediatric Kidney Care in the United Kingdom.

BACKGROUND AND OBJECTIVES: Pre-emptive kidney transplantation is advocated as best practice for children with kidney failure who are transplant eligible; however, it is limited by late presentation. We aimed to determine whether socioeconomic deprivation and/or geographic location (distance to the center and rural/urban residence) are associated with late presentation, and to what degree these factors could explain differences in accessing pre-emptive transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study using prospectively collected United Kingdom Renal Registry and National Health Service Blood and Transplant data from January 1, 1996 to December 31, 2016 was performed. We included children aged >3 months to ≤16 years at the start of KRT. Multivariable logistic regression models were used to determine associations between the above exposures and our outcomes: late presentation (defined as starting KRT within 90 days of first nephrology review) and pre-emptive transplantation, with a priori specified covariates. RESULTS: Analysis was performed on 2160 children (41% females), with a median age of 3.8 years (interquartile range, 0.2-9.9 years) at first nephrology review. Excluding missing data, 478 were late presenters (24%); 565 (26%) underwent pre-emptive transplantation, none of whom were late presenting. No association was seen between distance or socioeconomic deprivation with late presentation, in crude or adjusted analyses. Excluding late presenters, greater area affluence was associated with higher odds of pre-emptive transplantation, (odds ratio, 1.20 per quintile greater affluence; 95% confidence interval, 1.10 to 1.31), with children of South Asian (odds ratio, 0.52; 95% confidence interval, 0.36 to 0.76) or Black ethnicity (odds ratio, 0.31; 95% confidence interval, 0.12 to 0.80) less likely to receive one. A longer distance to the center was associated with pre-emptive transplantation on crude analyses; however, this relationship was attenuated (odds ratio, 1.02 per 10 km; 95% confidence interval, 0.99 to 1.05) in the multivariable model. CONCLUSIONS: Socioeconomic deprivation or geographic location are not associated with late presentation in children in the United Kingdom. Geographic location was not independently associated with pre-emptive transplantation; however, children from more affluent areas were more likely to receive a pre-emptive transplant.

Associations with Wellbeing and Medication Adherence in Young Adults Receiving Kidney Replacement Therapy.

BACKGROUND AND OBJECTIVES: Young adults receiving kidney replacement therapy (KRT) have impaired quality of life and may exhibit low medication adherence. We tested the hypothesis that wellbeing and medication adherence are associated with psychosocial factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a cross-sectional online survey for young adults on KRT. Additional clinical information was obtained from the UK Renal Registry. We compared outcomes by treatment modality using age- and sex-adjusted regression models, having applied survey weights to account for response bias by sex, ethnicity, and socioeconomic status. We used multivariable linear regression to examine psychosocial associations with scores on the Warwick-Edinburgh Mental Wellbeing Scale and the eight-item Morisky Medication Adherence Scale. RESULTS: We recruited 976 young adults and 64% responded to the survey; 417 (71%) with transplants and 173 (29%) on dialysis. Wellbeing was positively associated with extraversion, openness, independence, and social support, and negatively associated with neuroticism, negative body image, stigma, psychologic morbidity, and dialysis. Higher medication adherence was associated with living with parents, conscientiousness, physician access satisfaction, patient activation, age, and male sex, and lower adherence was associated with comorbidity, dialysis, education, ethnicity, and psychologic morbidity. CONCLUSIONS: Wellbeing and medication adherence were both associated with psychologic morbidity in young adults. Dialysis treatment is associated with poorer wellbeing and medication adherence.

Young adults' perspectives on living with kidney failure: a systematic review and thematic synthesis of qualitative studies.

INTRODUCTION: Young adults fare worse than younger adolescents or older adults on a broad range of health indicators. Those with a chronic illness such as renal failure are a particularly vulnerable group, who experience poor outcomes compared with both children and older adults. Understanding how being in receipt of renal replacement therapy (RRT) affects the lives of young adults might help us to better prepare and support these individuals for and on RRT, and improve outcomes. This study aimed to synthesise research describing young adults' experiences of the psychosocial impact of kidney failure and RRT. DESIGN: A systematic literature review identified qualitative research reporting the perspectives of people aged 16-30 years receiving RRT on the psychosocial impact of renal failure. Electronic databases (including Medline/EMBASE/PsycINFO/ASSIA) were searched to November 2017 for full-text papers. The transparency of reporting of each study was assessed using the Consolidated Criteria for Reporting Qualitative Health Research (COREQ) framework. Quality was assessed using the Critical Appraisal Skills Programme qualitative checklist. An inductive thematic synthesis was undertaken. PARTICIPANTS: Seven studies from five different countries were included, comprising 123 young adults receiving RRT. RESULTS: Comprehensiveness of reporting was variable: studies reported 9-22 of the 32 COREQ-checklist items.Three global themes about the impact of kidney failure on young adults were identified: (1) difference desiring normality, (2) thwarted or moderated dreams and ambitions, and (3) uncertainty and liminality. These reflected five organising themes: (1) physical appearance and body image, (2) activity and participation, (3) educational disruption and underachievement, (4) career ambitions and employment difficulties, and (5) social isolation and intimate relationships. CONCLUSIONS: Across different countries and different healthcare settings, young adults on RRT experience difference and liminality, even after transplantation. Tailored social and psychological support is required to allow young adults to experience wellness while in receipt of RRT, and not have life on hold.

Gonadotrophin abnormalities in an infant with Lowe syndrome.

SUMMARY: This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic-pituitary-gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management. LEARNING POINTS: Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

Sociodemographic, Psychologic Health, and Lifestyle Outcomes in Young Adults on Renal Replacement Therapy.

BACKGROUND AND OBJECTIVES: Young adults receiving RRT face additional challenges in life. The effect of established kidney failure on young adulthood is uncertain. We aimed to establish the psychosocial and lifestyle status of young adults receiving RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a systematic review and meta-analysis of 16-30-year olds receiving RRT compared with the general population. We selected randomized, controlled trials; cohort studies; or cross-sectional studies without language restriction and extracted proportions of sociodemographic and lifestyle outcomes or validated psychologic health tests producing quality of life, wellbeing, and self-esteem scores. We undertook random effects meta-analysis. RESULTS: There were 60 studies with a total of 15,575 participants. Studies were largely single-center cross-sectional studies of those transplanted in childhood. Compared with healthy peers, young adults on RRT had lower quality of life, which was worse for patients on dialysis (seven studies: standardized mean difference, -1.01; 95% confidence interval [95% CI], -1.32 to -0.70) compared with patients with transplants (nine studies: standardized mean difference, -0.42; 95% CI, -0.64 to -0.20). They were more likely to be unemployed (seven studies: relative risk, 1.89; 95% CI, 1.47 to 2.44) and live in the family home (two studies: relative risk, 1.84; 95% CI, 1.40 to 2.43). They were less likely to be married or have a partner (four studies: relative risk, 0.71; 95% CI, 0.53 to 0.95). Higher education (three studies: relative risk, 1.05; 95% CI, 0.73 to 1.51), alcohol abstinence (three studies: relative risk, 1.96; 95% CI, 0.84 to 4.67), and smoking status (two studies: relative risk, 0.72; 95% CI, 0.36 to 1.44) did not differ. Results were limited by high heterogeneity and a small evidence base, biased toward surviving patients. CONCLUSIONS: Established kidney failure is associated with lower quality of life in young people and limited employment, independence, and relationships compared with healthy peers. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_10_19_CJASNPodcast_17_12_.mp3.

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

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.

A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.

Recent molecular insights have established the podocyte as a key component of the glomerular filtration barrier, and hence an important common pathway in proteinuric diseases. A conditionally immortalized human podocyte cell line has been developed by transfection with the temperature-sensitive SV40-T gene. These cells proliferate at the "permissive" temperature (33 degrees C). After transfer to the "nonpermissive" temperature (37 degrees C), they entered growth arrest and expressed markers of differentiated in vivo podocytes, including the novel podocyte proteins, nephrin, podocin, CD2AP, and synaptopodin, and known molecules of the slit diaphragm ZO-1, alpha-, beta-, and gamma-catenin and P-cadherin. The differentiation was accompanied by a growth arrest and the upregulation of cyclin-dependent kinase inhibitors, p27 and p57, as well as cyclin D(1), whereas cyclin A was downregulated. These data are consistent with cell cycle protein expression during podocyte maturation in vivo. In conclusion, the development of this cell line provides a new tool in the study of podocyte biology, which will enable accurate assessment of the behavior of these complex cells in health and disease.