Reliability of different estimated glomerular filtration rate as measures of renal function in children with sickle cell disease.

BACKGROUND: There is no reliable marker for detecting early renal disease in early children with sickle cell disease (SCD). Estimation of glomerular filtration rate (eGFR) as derived from the height/plasma creatinine formula is dependent on the accuracy of the creatinine analytical method used. The aim of this study was to evaluate different equations for eGFR. METHODS: Children aged 5-16 years recruited. mGFR was obtained using plasma disappearance of Inutest/Iohexol, serum creatinine (SCr) was measured either by standard laboratory method or by tandem mass spectrometry (MSMS). Estimated GFR was then calculated either by "Bedside Schwartz method" or by the full-age spectrum (FAS) equation. FINDINGS: A total of 79 patients (mean age 9.8 ± 4.0 years). A revised eGFR constant was calculated for Schwartz equation from the slope of the plot of height/plasma creatinine versus mGFR. Mean values for mGFR (132.7 ± 32.1 ml/min/1.73m2) and eGFR methods compared: eGFR from standard SCr was significantly higher (144.2 ± 37.3 ml/min/1.73m2, p = 0.008). The MSMS eGFR showed the lowest SD (SD = 27.5), while both FAS eGFR and FAS-height eGFR showed the highest correlation coefficient (r = 0.67). INTERPRETATION: eGFR calculation based on height and SCr determined with MSMS traceable creatinine is more reliable than Schwartz formula using jaffe/enzymatic methods in SCD children.

Acute kidney injury in children with chronic kidney disease is associated with faster decline in kidney function.

BACKGROUND: This study aimed to investigate the association of acute kidney injury (AKI) with change in estimated glomerular filtration rate (eGFR) in children with advanced chronic kidney disease (CKD). METHODS: Single centre, retrospective longitudinal study including all prevalent children aged 1-18 years with nondialysis CKD stages 3-5. Variables associated with CKD were analysed for their potential effect on annualised eGFR change (ΔGFR/year) following multiple regression analysis. Composite end-point including 25% reduction in eGFR or progression to kidney replacement therapy was evaluated. RESULTS: Of 147 children, 116 had at least 1-year follow-up in a dedicated CKD clinic with mean age 7.3 ± 4.9 years with 91 (78.4%) and 77 (66.4%) with 2- and 3-year follow-up respectively. Mean eGFR at baseline was 29.8 ± 11.9 ml/min/1.73 m2 with 79 (68%) boys and 82 (71%) with congenital abnormalities of kidneys and urinary tract (CAKUT). Thirty-nine (33.6%) had at least one episode of AKI. Mean ΔGFR/year for all patients was - 1.08 ± 5.64 ml/min/1.73 m2 but reduced significantly from 2.03 ± 5.82 to - 3.99 ± 5.78 ml/min/1.73 m2 from youngest to oldest age tertiles (P < 0.001). There was a significant difference in primary kidney disease (PKD) (77% versus 59%, with CAKUT, P = 0.048) but no difference in AKI incidence (37% versus 31%, P = 0.85) between age tertiles. Multiple regression analysis identified age (ß = - 0.53, P < 0.001) and AKI (ß = - 3.2, P = 0.001) as independent predictors of ΔGFR/year. 48.7% versus 22.1% with and without AKI reached composite end-point (P = 0.01). CONCLUSIONS: We report AKI in established CKD as a predictor of accelerated kidney disease progression and highlight this as an additional modifiable risk factor to reduce progression of kidney dysfunction. Graphical abstract.

Vitamin and trace element concentrations in infants and children with chronic kidney disease.

BACKGROUND: There are limited data regarding vitamin and trace element blood concentrations and supplementation needs in children with non-dialysis stages 3-5 of chronic kidney disease (CKD). METHODS: Retrospective cross-sectional review for nutritional blood concentrations measured over a recent 2-year period. In our CKD clinics, nutritional bloods including copper, zinc, selenium and vitamin A, vitamin E, active vitamin B12 and folate are monitored annually. Vitamin D status is monitored every 6-12 months. RESULTS: We reviewed 112 children (70 boys) with median (IQ1, IQ3) age 8.97 (4.24, 13.80) years. Estimated median (IQ1, IQ3) GFR (mL/min/1.73 m2) was 28 (21, 37). Vitamin A, active vitamin B12 and vitamin E concentrations were within normal range in 19%, 23% and 67% respectively, with all others being above normal range. Vitamin D blood concentrations were within desired range for 85% (15% had low levels) and folate blood concentrations were within normal range in 92%, with the remainder above or below target. For trace elements, 60%, 85% and 87% achieved normal ranges for zinc, selenium and copper respectively. Deficiencies were seen for zinc (35%), copper (7%), folate (3%) and selenium (1%), whilst 5%, 6% and 14% had zinc, copper and selenium levels above normal ranges. CONCLUSIONS: Several vitamin and trace element blood concentrations were outside normal reference ranges. Monitoring vitamin D and zinc blood concentrations is indicated due to the percentages with low levels in this group. Targeted vitamin and trace element supplementation should be considered where indicated rather than commencing multivitamin and/or mineral supplementation. Graphical abstract Vitamin and trace element concentrations in infants and children with non-dialysis chronic kidney disease.

Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy.

Autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) are emerging as biomarkers to classify membranous nephropathy (MN) and to predict outcome or response to treatment. Anti-THSD7A autoantibodies are detected by Western blot and indirect immunofluorescence test (IIFT). Here, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) optimized for quantitative detection of anti-THSD7A autoantibodies. Among 1012 biopsy-proven MN patients from 6 cohorts, 28 THSD7A-positive patients were identified by ELISA, indicating a prevalence of 2.8%. By screening additional patients, mostly referred because of PLA2R1-unrelated MN, we identified 21 more cases, establishing a cohort of 49 THSD7A-positive patients. Twenty-eight patients (57%) were male, and male patients were older than female patients (67 versus 49 years). Eight patients had a history of malignancy, but only 3 were diagnosed with malignancy within 2 years of MN diagnosis. We compared the results of ELISA, IIFT, Western blot, and biopsy staining, and found a significant correlation between ELISA and IIFT titers. Anti-THSD7A autoantibodies were predominantly IgG4 in all patients. Eight patients were double positive for THSD7A and PLA2R1. Levels of anti-THSD7A autoantibodies correlated with disease activity and with response to treatment. Patients with high titer at baseline had poor clinical outcome. In a subgroup of patients with serial titers, persistently elevated anti-THSD7A autoantibodies were observed in patients who did not respond to treatment or did not achieve remission. We conclude that the novel anti-THSD7A ELISA can be used to identify patients with THSD7A-associated MN and to monitor autoantibody titers during treatment.

Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland.

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange-treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody-targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody-mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.

Relationship of FGF23 to indexed left ventricular mass in children with non-dialysis stages of chronic kidney disease.

BACKGROUND: The aim of this study was to evaluate the association of serum intact fibroblast growth factor 23 (FGF23) concentrations with indexed left ventricular mass in children with non-dialysis stages 3-5 of chronic kidney disease (CKD). METHODS: The study cohort comprised 83 children (51 boys; mean age 12.1 ± 3.2 years) with a mean estimated glomerular filtration rate (eGFR) of 32.3 ± 14.6 ml/min/1.73 m(2) who underwent clinic and ambulatory blood pressure measurement (ABPM), echocardiography and evaluation of biochemical markers of CKD-associated mineral bone disease. RESULTS: The mean left ventricular mass index (LVMI) was 35.9 ± 8.5 g/m(2.7) (± standard deviation), with 30 (36.1 %) children showing left ventricular hypertrophy (LVH), all eccentric, as defined using age-specific criteria. For all subjects, the mean FGF23 concentration was 142.2 ± 204.4 ng/l and the normalised distribution following log transformation was 1.94 ± 0.39. There was significant univariate correlation of LVMI with GFR, body mass index (BMI) z-score and calcium intake, but not with 24-h systolic ABPM z-score, log intact parathyroid hormone or log FGF23. On multivariate analysis following adjustment for confounders, only elemental calcium content (g/kg/day) estimated from prescribed calcium-based phosphate binder dose (ß = 154.9, p < 0.001) and BMI z-score (ß = 2.397, p = 0.003) maintained a significant positive relationship with LVMI (model r (2) = 0.225). CONCLUSIONS: We observed no significant relationship of FGF23 with LVMI. Larger studies in children are needed to clarify the roles of calcium-containing phosphate binders and FGF23 with LV mass and their roles in the evolution of the development of adverse cardiovascular outcomes.

Subarachnoid haemorrhage and cerebral vasculopathy in a child with sickle cell anaemia.

Stroke in sickle cell anaemia (SCA) is either infarctive or haemorrhagic in nature. In childhood, over 75% of strokes in SCA are infarctive. We present an adolescent with SCA who developed hypertension at the age of 13, and was treated with lisinopril. Sixteen months later she was found in cardiorespiratory arrest and died on arrival in hospital. The last transcranial Doppler scan performed 6 months before her death and a brain MRI were reported normal. The autopsy discovered massive subarachnoid haemorrhage in association with vascular damage in the circle of Willis arteries. The case highlights a cause of haemorrhagic stroke, the first reported association between hypertension, SCA and a histopathologically proven cerebral vasculopathy. The difficulties in the management of haemorrhagic stroke and the poor outcome in SCA are discussed.

The demographic characteristics of children with chronic kidney disease stages 3-5 in South East England over a 5-year period.

OBJECTIVE: To analyse the demographics of children with moderate to severe chronic kidney disease (CKD) stages 3-5 over a 5-year period for the population of South East England. METHODS: Retrospective study of all children <18 years of age with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) managed at Evelina Children's Hospital, London from 2005 to 2009. eGFR was estimated using the Schwartz formula, and stages of CKD were defined using Kidney Disease Outcome Quality Initiative criteria. We excluded all patients with a functioning kidney transplant. RESULTS: There were 293 children (58% male) with a median (IQR) age of 6.7 (2.3, 12.1) years; 288 were aged <16 years and five 16-18 years at first presentation. The mean incidence and prevalence of children <16 years with CKD stage 3-5 during the 5-year study period was 17.5 and 90.0 per million age-related population (pmarp), respectively. There was a marked increase in incidence and prevalence over the 5 years (incidence 8.4 to 25.2 pmarp; prevalence 79.5 to 104.7 pmarp). There was an initial peak in children presenting under 2 years of age (48/141, 34%) due to congenital renal disease, and a second peak in the 12-15.9-year age group (32/141, 23%) due to glomerulonephritides. Forty-five children (15%) were transplanted, and 22 (8%) transitioned to adult care. There were seven deaths giving a death rate of 0.84 per 100 patient-years. CONCLUSIONS: We observed a steady increase in the incidence and prevalence of children with CKD stage 3-5. As a result of improved management, the majority of children with CKD will proceed to kidney transplantation, transition to adult nephrology services, and continue to require lifelong medical care.

Investigating the role of cardiovascular biomarkers in children with pre-dialysis chronic kidney disease: a substitute to echocardiography to detect increased left ventricular mass?

BACKGROUND: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). METHODS: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3-5 of CKD. RESULTS: Of 73 children aged 5-18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. CONCLUSIONS: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD.

Emergencies during home births.

This article reflects on how community midwifery skills days have assisted community midwives to develop confidence in managing unexpected emergencies at home births, and how team work, communication and working in partnership have supported women in their choices for birth.

Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5.

BACKGROUND: The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF-23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. METHODS: In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 ± 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. RESULTS: Fourteen (19.7%) patients had normal FGF-23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 ± 0.4 ng/L. Log FGF-23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. CONCLUSIONS: Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship.

Factors affecting success of blood pressure measurements during ambulatory blood pressure monitoring in children with renal disease.

AIM: To analyse blood pressure characteristics during 24-hour ambulatory blood pressure monitoring in children and to assess factors that influence its success over 24 hours and during patient-recorded awake (DAY) and sleep (NIGHT) periods. METHODS: A total of 169 consecutive ambulatory blood pressure monitoring studies were conducted in 154 patients over 30 months. For each ambulatory study, we measured the percentage of successful measurements both at the first attempt (S-initial%) and following any automated repeat attempt if initial attempts had failed (S-final%). These were measured over 24-hour, DAY, and NIGHT periods. RESULTS: We found that blood pressure measurements at NIGHT were more successful than measurements attempted during the DAY (p<0.05). There was no influence of age, gender, height, weight, body mass index and estimated glomerular filtration rate with the proportion of successful measurements during the 24-hour, DAY, and NIGHT periods. On stepwise multiple regression analysis, the indexed mean systolic blood pressure over 24 hours was the only factor having a significant influence on the proportion of successful measurements over the 24-hour and DAY periods, although it only accounted for three-tenths of the variance; it had no influence on the overall success of measurements at NIGHT. CONCLUSION: Ambulatory blood pressure monitoring in children provides reliable data both during the patient's awake and sleep periods with higher success of measurements at NIGHT as opposed to DAY periods.

Blood pressure control and left ventricular mass in children with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Heart disease is a major cause of death in young adults with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) is common and is associated with hypertension. The aims of this study were to evaluate whether there is a relationship between LVH and BP in children with CKD and whether current targets for BP control are appropriate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this single-center cross-sectional study, 49 nonhypertensive children, (12.6 ± 3.0 years, mean GFR 26.1 ± 12.9 ml/min per 1.73 m²) underwent echocardiographic evaluation and clinic and 24-hour ambulatory BP monitoring. LVH was defined using age-specific reference intervals for left ventricular mass index (LVMI). Biochemical data and clinic BP for 18 months preceding study entry were also analyzed. RESULTS: The mean LVMI was 37.8 ± 9.1 g/m²·7, with 24 children (49%) exhibiting LVH. Clinic BP values were stable over the 18 months preceding echocardiography. Patients with LVH had consistently higher BP values than those without, although none were overtly hypertensive (> 95th percentile). Multiple linear regression demonstrated a strong relationship between systolic BP and LVMI. Clinic systolic BP showed a stronger relationship than ambulatory measures. Of the confounders evaluated, only elemental calcium intake yielded a consistent, positive relationship with LVMI. CONCLUSIONS: LVMI was associated with systolic BP in the absence of overt hypertension, suggesting that current targets for BP control should be re-evaluated. The association of LVMI with elemental calcium intake questions the appropriateness of calcium-based phosphate binders in this population.

Congenital disorders of glycosylation: a rare cause of nephrotic syndrome.

Congenital disorders of glycosylation (CDG) are inborn errors of metabolism presenting with multi-system organ involvement due to defective glycosylation of glycoproteins. We report here a case of microcephaly, hypotonia, seizure disorder and severe developmental delay since infancy in whom screening for CDG with transferring isoelectric focussing (TIEF) revealed a type I pattern. Following investigation, the specific defect in glycosylation remains to be identified; hence, a diagnosis of CDG Ix (type unknown) was made. At the age of 15-months the patient developed nephrotic syndrome and renal biopsy indicated a histopathological diagnosis of diffuse mesangial sclerosis on histopathology. Since cases of CDG Ix may often develop hypoalbuminaemia secondary to malabsorption or liver disease, this case highlights the need for additional regular monitoring for glomerular proteinuria, and indicates that a diagnosis of nephrotic syndrome should be considered in all types of CDG. Furthermore, we propose that early treatment with anti-proteinuric agents may be necessary to limit proteinuria and slow disease progression.

Bilateral laparoscopic nephrectomy with simultaneous peritoneal dialysis: a new era.

Peritoneal dialysis is the treatment of choice in children with end-stage renal failure who are awaiting renal transplantation. Traditionally patients requiring bilateral nephrectomy spent time on haemodialysis prior to being converted to peritoneal dialysis during a separate operation. Bilateral synchronous retroperitoneoscopic nephrectomy with the initiation of or return to peritoneal dialysis in the immediate postoperative period was performed on three patients with end-stage renal failure in our unit. The indications for bilateral nephrectomy were persistent heavy proteinuria in two children and difficult to control hypertension in the third. Bilateral laparoscopic nephrectomy was performed with the patients in the prone position. Two of the children were then placed in a supine position and a tunneled peritoneal dialysis catheter was inserted in the standard open fashion. The postoperative complications included a peritoneal catheter line breach requiring intraperitoneal antibiotics and a fever that was culture negative and settled spontaneously. This technique allows for immediate peritoneal dialysis, with the added benefit of reduced postoperative pain and improved cosmetic appearance.

Management of renal vascular disease in neurofibromatosis type 1 and the role of percutaneous transluminal angioplasty.

BACKGROUND: The effectiveness of percutaneous transluminal angioplasty (PTA) in renal artery stenosis (RAS) associated with neurofibromatosis type 1 (NF1) has not been established. A review of the literature revealed 14 studies, mainly case reports, of which a total of 16 patients had been treated with PTA, all prior to any surgery being undertaken. METHODS: A retrospective case review of 10 children with renal vascular disease secondary to NF was conducted to evaluate the outcome of different treatment modalities, including PTA. Four patients had unilateral disease, while six had bilateral disease, which was associated with middle aortic syndrome in three. Treatment was a combination of antihypertensive drug therapy, PTA and surgery. PTA was performed 15 times on six patients, nine procedures prior to surgery. RESULTS: The success rate for PTA on primary stenoses was 33% with improvement in blood pressure (BP) control in another 33%. Angioplasties performed on stenoses post-surgery had a success rate of 67%. There were no major complications and PTA had no adverse effect on subsequent surgery. The pre-surgery results obtained at a tertiary referral centre are consistent with those reported in the literature. CONCLUSION: PTA is a safe and moderately effective treatment modality for RAS secondary to NF1. Although there is only limited success in primary stenoses as there is no adverse effect on subsequent surgery we feel it should be considered as first line management when clinically indicated.