Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up. RESULTS: The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

The extent of kidney involvement in paediatric tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis (TSC)-associated kidney disease is a leading cause of mortality in adults with TSC. This study aimed to understand TSC features in children, particularly kidney involvement, to inform clinical care for this specific group. METHODS: This retrospective cohort study included all paediatric (< 19 years) TSC cases at a large tertiary paediatric nephrology centre. Relevant data were collected from patients' records, statistical analyses were performed to identify associations between variables, survival probabilities were estimated with Kaplan‒Meier curves, and log-rank tests were conducted to assess survival differences among genetic mutations. RESULTS: A total of 182 children with TSC were included. Among the 145 children with available kidney imaging data, 78.6% (114/145) exhibited kidney lesions. Angiomyolipomas (AMLs) were significantly more prevalent in the TSC2 mutation group (p = 0.018). Children with TSC2 mutations generally had poorer lesion-free survival than those with TSC1 mutations, but this difference was only significant for AMLs (p = 0.030). The change in size of largest AMLs increased with age and doubled in children above 9 years; a similar pattern was observed when stratified by genetic mutation. In contrast, kidney cysts exhibited two peaks: one in children under 5 years (2.31 mm/year) and the second in children between 15-19 years (2.82 mm/year). Chronic kidney disease was observed in 12.3% (10/81) of children, and high-risk AMLs above 3 cm were observed in 9% (13/145). CONCLUSIONS: While TSC kidney disease emerges later in the disease course than neurological features, our findings emphasise the importance of kidney surveillance during childhood, including routine kidney imaging, kidney function, and blood pressure monitoring.

Congenital anomalies of the kidney and urinary tract: antenatal diagnosis, management and counselling of families.

Congenital anomalies of the kidney and urinary tract are collectively one of the most commonly diagnosed antenatal conditions. Clinicians have several tools available to diagnose anomalies, including imaging, biomarkers, family history and genetic studies. In certain cases, antenatal interventions such as vesico-amniotic shunting may be considered to improve postnatal outcomes.Congenital kidney anomalies detected antenatally can vary in clinical significance from almost no impact postnatally to significant morbidity and perinatal mortality. Prognosis broadly depends on kidney size, structure and amount of amniotic fluid, alongside genetics and family history, and progression on subsequent scans. It is important to counsel parents appropriately using a parent-focused and personalised approach. The use of a multidisciplinary team should always be considered.

Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis.

The purpose of this study is to determine the predictive factors of tuberous sclerosis complex (TSC)-associated kidney disease and its progression in children. Retrospective review of children with TSC in a tertiary children's hospital was performed. Relevant data were extracted, and Cox proportional hazards regression was used to establish predictors of kidney lesions. Logistic regression was conducted to identify factors predicting chronic kidney disease (CKD) and high-risk angiomyolipomas (above 3 cm). Kidney imaging data were available in 145 children with TSC; of these, 79% (114/145) had abnormal findings. The only significant predictive factor for cyst development was being female (HR = 0.503, 95% CI 0.264-0.956). Being female (HR = 0.505, 95% CI 0.272-0.937) and underweight (HR = 0.092, 95% CI 0.011-0.800) both lowers the risk of having angiomyolipomas, but TSC2 mutations (HR = 2.568, 95% CI 1.101-5.989) and being obese (HR = 2.555, 95%CI 1.243-5.255) increases risks. Ten (12%) of 81 children with kidney function tested demonstrate CKD stages II-V, and only angiomyolipomas above 3 cm predict CKD. Additionally, 13/145 (9%) children had high-risk angiomyolipomas, whereby current age (adjusted odds ratio (aOR) 1.015, 95% CI 1.004-1.026) and being overweight/obese (aOR 7.129, 95% CI 1.940-26.202) were significantly associated with angiomyolipomas above 3 cm. CONCLUSIONS: While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted. WHAT IS KNOWN: • Gender and genotype are well-studied predictive factors in TSC kidney disease. WHAT IS NEW: • Nutritional status may influence the development and the progression of kidney lesions in children with TSC and should not be overlooked. • Management guidelines of TSC-associated kidney disease can address nutritional aspects.

Should we screen for intracranial aneurysms in children with autosomal dominant polycystic kidney disease?

This is an overview of the challenges associated with screening for asymptomatic intracranial aneurysms (ICA) in children with autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most common inherited kidney disease affecting 1 in 1,000 people. ICAs are an extra-kidney manifestation of ADPKD, and while the exact pathophysiology of how they develop is unknown, we know that they more commonly occur in the adult rather than paediatric population. ICAs can be found in up to 9-11.5% of adults with ADPKD, but ICA rupture remains a rare event in adults with an incidence of 0.04 per 100 patient years. ICA size is an important factor in determining the risk of aneurysm rupture and therefore affects the decision on intervention in asymptomatic adults. For some, unruptured aneurysms cause no clinical significance, but those that rupture can be associated with devastating morbidity and mortality. Therefore, if detected, the treatment for unruptured ICAs is usually endovascular coiling, alongside recognising the importance of preventative interventions such as hypertension management. There are, however, no current guidelines for either adult or paediatric patients with ADPKD supporting regular screening for asymptomatic ICAs, although there is a suggestion for individualised practice, for example, with those with a positive family history. The UK clinical guidelines for ADPKD in children make research recommendations due to a lack of published literature, which in itself indicates that ICA rupture is an extremely rare phenomenon in children.

Safeguarding children and young people requiring kidney replacement therapy: challenges and potential opportunities.

Kidney replacement therapy (KRT) makes considerable physical and psychological demands on children, young people and their families. The impact can be wide-ranging, affecting education, employment, mental health, finances and relationships for both child and caregiver. It is vitally important for those working with these families to recognise the psychosocial challenges they face and to know the range of interventions available. This article explores the psychosocial impact of KRT, considering opportunities to minimise risk and optimise outcomes for children, young people and their families.

Commentary on the NICE guideline on renal replacement therapy and conservative management.

BACKGROUND: NICE Guideline NG107, "Renal replacement therapy and conservative management" (Renal replacement therapy and conservative management (NG107); 2018:1-33) was published in October 2018 and replaced the existing NICE guideline CG125, "Chronic Kidney Disease (Stage 5): peritoneal dialysis" (Chronic kidney disease (stage 5): peritoneal dialysis | Guidance | NICE; 2011) and NICE Technology Appraisal TA48, "Guidance on home compared with hospital haemodialysis for patients with end-stage renal failure"(Guidance on home compared with hospital haemodialysis for patients with end-stage renal failure (Technology appraisal guideline TA48); 2002) The aim of the NICE guideline (NG107) was to provide guidance on renal replacement therapy (RRT), including dialysis, transplant and conservative care, for adults and children with CKD Stages 4 and 5. The guideline is extremely welcomed by the Renal Association and it offers huge value to patients, clinicians, commissioners and key stakeholders. It overlaps and enhances current guidance published by the Renal Association including "Haemodialysis" (Clinical practice guideline: Haemodialysis; 2019) which was updated in 2019 after the publication of the NICE guideline, "Peritoneal Dialysis in Adults and Children" (Clinical practice guideline: peritoneal Dialysis in adults and children; 2017) and "Planning, Initiation & withdrawal of Renal Replacement Therapy" (Clinical practice guideline: planning, initiation and withdrawal of renal replacement therapy; 2014) (at present there are no plans to update this guideline). There are several strengths to NICE guideline NG107 and we agree with and support the vast majority of recommendation statements in the guideline. This summary from the Renal Association discusses some of the key highlights, controversies, gaps in knowledge and challenges in implementation. Where there is disagreement with a NICE guideline statement, we have highlighted this and a new suggested statement has been written.

Catch-up growth in children with chronic kidney disease started on enteral feeding after 2 years of age.

BACKGROUND: Enteral feeding by tube in chronic kidney disease (CKD) before 2 years of age improves growth. Whether it is effective after this age is unknown. We assessed whether height and weight SDS changed after tube feeding was started in children with CKD above 2 years of age. METHODS: Retrospective study of pre-transplant, pre-pubertal children (< 11 years) with CKD stages 2-5 started on nasogastric tube or gastrostomy feeds for the first time after age 2 years. Children were identified by searching dietetic records and the renal database. Children on growth hormone were excluded. Height, weight, and BMI were documented 1 year prior to and at the start of tube feeds, and after 1 and 2 years. Data collection ceased at transplantation. RESULTS: Fifty children (25 male) were included. The median (range) age at start of tube feeds was 5.6 (2.1-10.9) years. Sixteen children were dialysed (1 haemodialysis, 15 peritoneal dialysis); 34 predialysis patients had a median (range) eGFR of 22 (6-88) ml/min/1.73 m2. Overall height SDS (Ht SDS) improved from - 2.39 to - 2.27 at 1 year and - 2.18 after 2 years (p = 0.02). BMI SDS improved from - 0.72 to 0.23 after 1 year and was 0.09 after 2 years of enteral feeding (p < 0.0001). Height SDS improved more in children aged 2-6 years (- 2.13 to - 1.68, p = 0.03) and in children not on dialysis (- 2.33 to - 1.99, p = 0.002). CONCLUSIONS: Enteral tube feeding commenced after 2 years of age in prepubertal children with CKD improves height and weight SDS, with stability of BMI during the second year. Younger children and those not on dialysis had the greatest benefit.

Central blood pressure and measures of early vascular disease in children with ADPKD.

BACKGROUND: There is growing recognition of hypertension in a significant proportion of children with ADPKD. In this study, we assessed blood pressure and cardiovascular status in children with ADPKD. METHODS: A prospective two-centre observational study of children (< 18 years) with ADPKD was compared against age- and BMI-matched healthy controls. Children underwent peripheral BP (pBP) measured using an aneroid sphygmomanometer and auscultation, 24-h ambulatory BP monitoring (ABPM), non-invasive central BP (cBP) measurement, carotid-femoral pulse wave velocity (PWVcf) measured using applanation tonometry and measurement of indexed left ventricular mass (LVMI) using echocardiography. This study received independent ethical approval. RESULTS: Forty-seven children with ADPKD and 49 healthy controls were recruited (median age 11 years vs. 12 years). Children with ADPKD had significantly higher systolic pBP (mean 112 ± 13.5 mmHg vs. 104 ± 11 mmHg, p < 0.001), higher systolic cBP (mean 97 ± 12.8 mmHg vs. 87 ± 9.8 mmHg, p < 0.001) and lower pulse pressure amplification ratio (1.59 ± 0.2 vs. 1.67 ± 0.1, p = 0.04) compared to healthy children. Thirty-five percent of children with ADPKD showed a lack of appropriate nocturnal dipping on 24-h ABPM. There was no difference in PWVcf between children with ADPKD and healthy children (mean 5.74 ± 1 m/s vs. 5.57 ± 0.9 m/s, p = 0.46). Those with ADPKD had a significantly higher LVMI (mean 30.4 ± 6.6 g/m2.7 vs. 26.2 ± 6.2 g/m2.7, p = 0.01). CONCLUSIONS: These data highlight the high prevalence of hypertension in children with ADPKD, also demonstrating early cardiovascular dysfunction with increased LVMI and reduced PP amplification despite preserved PWVcf, when compared with healthy peers. These early cardiovascular abnormalities are likely to be amenable to antihypertensive therapy, reinforcing the need for routine screening of children with ADPKD.

Clinical practice guideline monitoring children and young people with, or at risk of developing autosomal dominant polycystic kidney disease (ADPKD).

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is thought to affect about 1 in 1000 people in the UK. ADPKD causes a progressive decline in kidney function, with kidney failure tending to occur in middle age. Children and young people with ADPKD may not have any symptoms. However they may have high blood pressure, which may accelerate progression to later stages of chronic kidney disease.There is uncertainty and variation in how health professionals manage children and young people with confirmed or a family history of ADPKD, because of a lack of evidence. For example, health professionals may be unsure about when to test children's blood pressure and how often to monitor it in the hospital clinic or at the GP. They may have different approaches in recommending scanning or genetic testing for ADPKD in childhood, with some recommending waiting until the young person is mature enough to make this decision his or herself.This guideline is intended to help families affected by ADPKD by making sure that: health professionals with specialist knowledge in ADPKD offer you information on inheritance and potential benefits and harms of testing for ADPKD. the decision to test and the method of testing for ADPKD in children and young people is shared between you or your family and the health professionals blood pressure assessment is undertaken regularly in children and young people at risk of developing ADPKD.

Renal allograft survival rates in kidneys initially declined for paediatric transplantation.

BACKGROUND: The outcome of organs which have been declined for paediatric recipients is not known. This study aimed to determine the outcome of kidneys initially declined for paediatric recipients and establish renal allograft survival in kidneys that were eventually transplanted. METHODS: Data were obtained from the UK Transplant Registry for all donation after brain death (DBD) kidneys offered and declined to paediatric recipients (< 18 years) in the UK from 2009 to 2014. RESULTS: Eighty-two percent (503/615) of kidneys initially declined for paediatric transplantation were eventually transplanted, 7% (46/615) of kidneys went to paediatric recipients and 62% (384/615) of kidneys went to adult (kidney only) recipients. The remainder were used for multiple organ transplants. In the 46 kidneys that went to paediatric recipients, 1 and 3-year renal allograft survivals were 89% (95% CI 75.8-95.3%) and 82% (95% CI 67.1-90.6%), respectively. In the 384 kidneys given to adult kidney-only recipients, 1 and 3-year renal allograft survivals were 96% (95% CI 93.5-97.6%) and 94% (95% CI 90.7-96.1%), respectively. Eighty-four percent of the 204 children who initially had an offer declined on their behalf were eventually transplanted and have a functioning graft at a median 3-year follow-up. CONCLUSIONS: This study reports acceptable short-term renal allograft survival in kidneys that were initially declined for paediatric recipients and subsequently transplanted. Evidence-based guidelines are required to ensure that the most appropriate kidneys are selected for paediatric recipients.

Kidney donation after circulatory death: current evidence and opportunities for pediatric recipients.

Organ donation after circulatory death (DCD) has experienced a revival worldwide over the past 20 years, and is now widely practiced for kidney transplantation. Some previous concerns about these organs such as the high incidence of delayed graft function have been alleviated through evidence from adult studies. There are now a number of large adult cohorts reporting favorable 5-year outcomes for DCD kidney transplants, comparable to kidneys donated after brain death (DBD). This has resulted in a marked increase in the use of DCD kidneys for adult recipients in some countries and an increase in the overall number of kidney transplants. In contrast, the uptake of DCD kidneys for pediatric recipients is still low and concerns still exist over the longer-term outcomes of DCD organs. In view of the data from adult practice and the poor outcomes for children who stay on dialysis, DCD kidney transplantation should be offered as an option for children on the kidney transplant waiting list.

Paediatrics, insulin resistance and the kidney.

Systemic insulin resistance is becoming more prevalent in the young due to modern lifestyles predisposing to the metabolic syndrome and obesity. There is also evidence that there are critical insulin-resistant phases for the developing child, including puberty, and that renal disease per se causes systemic insulin resistance. This review considers the factors that render children insulin resistant, as well as the accumulating evidence that the kidney is an insulin-responsive organ and could be affected by insulin resistance.

Unilateral hypoplastic kidney - a novel highly penetrant feature of familial juvenile hyperuricaemic nephropathy.

BACKGROUND: Familial juvenile hyperuricaemic nephropathy is a rare inherited nephropathy with genetic heterogeneity. Categorised by genetic defect, mutations in uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1ß (HNF-1ß) genes as well as linkage to chromosome 2p22.1-21 have previously been identified. Knowledge of the genetics of this phenotype has provided important clues to developmental pathways in the kidney. CASE PRESENTATION: We report a novel phenotype, with the typical features of hyperuricemia and renal deterioration, but with the additional unexpected feature of unilateral renal hypoplasia. Mutation analyses of the existing known genes and genetic loci were negative indicating a new monogenic cause. Interestingly two cousins of the index case did not share the latter feature, suggesting a modifier gene effect. CONCLUSION: Unilateral renal hypo/aplasia is usually sporadic and relatively common, with no genetic cause to date identified. This reported pedigree reveals the possibility that a new, unknown renal developmental gene may be implicated in the FJHN phenotype.

A targeted gene panel illuminates pathogenesis in young people with unexplained kidney failure.

BACKGROUND: Kidney failure in young people is often unexplained and a significant proportion will have an underlying genetic diagnosis. National Health Service England pioneered a comprehensive genomic testing service for such circumstances accessible to clinicians working outside of genetics. This is the first review of patients using this novel service since October 2021, following its introduction into clinical practice. METHODS: The 'Unexplained Young-Onset End-Stage Renal Disease' (test-code R257) gene panel uses targeted next generation sequencing to analyse 175 genes associated with renal disease in patients under 36 years of age. All tests undertaken between October 2021 and February 2022 were reviewed. Phenotypic data were extracted from request forms and referring clinicians contacted where additional details were required. RESULTS: Seventy-one patients underwent R257 testing over the study period. Among them, 23/71 patients (32%) were confirmed to have a genetic diagnosis and 2/71 (3%) had a genetically suggestive variant. Nephronophthisis and Alport syndrome were the most common conditions identified, (4/23 (17%) with pathogenic variants in NPHP1 and 4/23 (17%) with pathogenic variants in COL4A3/COL4A4). Positive predictors of a genetic diagnosis included a family history of renal disease (60% of positive cases) and extra-renal disease manifestations (48% of positive cases). CONCLUSION: This is the first study to evaluate the R257 gene panel in unexplained young-onset kidney failure, freely accessible to patients meeting testing criteria in England. A genetic diagnosis was identified in 32% of patients. This study highlights the essential and expanding role that genomic testing has for children and families affected by renal disease today.

National recommendations for the management of children and young people with IgA vasculitis: a best available evidence, group agreement-based approach.

OBJECTIVE: IgA vasculitis (IgAV) is the most frequently experienced subtype of vasculitis seen in children. Most children fully recover, however, complications including chronic kidney disease are recognised. The aim of this project was to use a best available evidence, group agreement, based approach to develop national recommendations for the initial management of IgAV and its associated complications. METHODS: A fully representative multiprofessional guideline development group (GDG), consisting of 28 members, was formed and met monthly. Graded recommendations were generated using nationally accredited methods, which included a predefined scope, open consultation, systematic literature review, evidence appraisal, review of national or international guidelines and a period of open consultation. Audit measures and research priorities were incorporated. RESULTS: The IgAV GDG met over a 14-month period. A total of 82 papers were relevant for evidence synthesis. For the initial management, four topic areas were identified with five key questions generating six graded recommendations related to classification, specialist referral and musculoskeletal involvement. For the associated complications, five topic areas with 12 key questions generated 15 graded recommendations covering nephritis, gastrointestinal and testicular involvement, atypical disease and follow-up. Open consultation feedback was incorporated. The guidelines were endorsed by the UK Kidney Association and Royal College of Paediatrics and Child Health and are available online. CONCLUSION: Despite IgAV being a rare disease with limited evidence, a national standardised approach to the clinical management for children and young people has been achieved. This should unite approaches to care and act as a foundation for improvement.