Decline in Left Ventricular Early Systolic Function with Worsening Kidney Function in Children with Chronic Kidney Disease: Insights from the 4C and HOT-KID Studies.

INTRODUCTION: Adults with childhood-onset chronic kidney disease (CKD) have an increased risk of cardiovascular disease. First-phase ejection fraction (EF1), a novel measure of early systolic function, may be a more sensitive marker of left ventricular dysfunction than other markers in children with CKD. OBJECTIVE: To examine whether EF1 is reduced in children with CKD. METHODS: Children from the 4C and HOT-KID studies were stratified according to estimated glomerular filtration rate (eGFR). The EF1 was calculated from the fraction of left ventricular (LV) volume ejected up to the time of peak aortic flow velocity. RESULTS: The EF1 was measured in children ages 10.9 ± 3.7 (mean ± SD) years, 312 with CKD and 63 healthy controls. The EF1 was lower, while overall ejection fraction was similar, in those with CKD compared with controls and decreased across stages of CKD (29.3% ± 3.7%, 23.5% ± 4.5%, 19.8% ± 4.0%, 18.5% ± 5.1%, and 16.7% ± 6.6% in controls, CKD 1, 2, 3, and ≥ 4, respectively, P < .001). The relationship of EF1 to eGFR persisted after adjustment for relevant confounders (P < .001). The effect size for association of measures of LV structure or function with eGFR (SD change per unit change in eGFR) was greater for EF1 (ß = 0.365, P < .001) than for other measures: LV mass index (ß = -0.311), relative wall thickness (ß = -0.223), E/e' (ß = -0.147), and e' (ß = 0.141) after adjustment for confounders in children with CKD. CONCLUSIONS: Children with CKD exhibit a marked and progressive decline in EF1 with falling eGFR. This suggests that EF1 is a more sensitive marker of LV dysfunction when compared to other structural or functional measures and that early LV systolic function is a key feature in the pathophysiology of cardiac dysfunction in CKD.

Intensive compared with less intensive blood pressure control to prevent adverse cardiac remodelling in children with chronic kidney disease (HOT-KID): a parallel-group, open-label, multicentre, randomised, controlled trial.

BACKGROUND: Optimal target blood pressure to reduce adverse cardiac remodelling in children with chronic kidney disease is uncertain. We hypothesised that lower blood pressure would reduce adverse cardiac remodelling. METHODS: HOT-KID, a parallel-group, open-label, multicentre, randomised, controlled trial, was done in 14 clinical centres across England and Scotland. We included children aged 2-15 years with stage 1-4 chronic kidney disease-ie, an estimated glomerular filtration rate (eGFR) higher than 15 mL/min per 1·73 m2-and who could be followed up for 2 years. Children on antihypertensive medication were eligible as long as it could be changed to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) if they were not already receiving these therapies. Participants were randomly assigned (1:1) to standard treatment (auscultatory office systolic blood pressure target between the 50th and 75th percentiles) or intensive treatment (systolic target <40th percentile) by the chief investigator using a rapid, secure, web-based randomisation system. ACE inhibitors or ARBs were used as first-line agents, with the dose titrated every 2-4 weeks to achieve the target blood pressure levels. The primary outcome was mean annual difference in left ventricular mass index (LVMI) by echocardiography measured by a masked observer and was assessed in the intention-to-treat population, defined as all the children who underwent randomisation irrespective of the blood pressure reached. Secondary and safety outcomes were the differences between groups in mean left ventricular relative wall thickness, renal function, and adverse effects and were also assessed in the intention-to-treat population. This trial is registered with ISRCTN, ISRCTN25006406. FINDINGS: Between Oct 30, 2012, and Jan 5, 2017, 64 participants were randomly assigned to the intensive treatment group and 60 to the standard treatment group (median age of participants was 10·0 years [IQR 6·8-12·6], 69 [56%] were male and 107 [86%] were of white ethnicity). Median follow-up was 38·7 months (IQR 28·1-52·2). Blood pressure was lower in the intensive treatment group compared with standard treatment group (mean systolic pressure lower by 4 mm Hg, p=0·0012) but in both groups was close to the 50th percentile. The mean annual reduction in LVMI was similar for intensive and standard treatments (-1·9 g/m2·7 [95% CI -2·4 to -1·3] vs -1·2 g/m2·7 [-1·5 to 0·8], with a treatment effect of -0·7 g/m2·7 [95% CI -1·9 to 2·6] per year; p=0·76) and mean value in both groups at the end of follow-up within the normal range. At baseline, elevated relative wall thickness was more marked than increased LVMI and a reduction in relative wall thickness was greater for the intensive treatment group than for the standard treatment group (-0·010 [95% CI 0·015 to -0·006] vs -0·004 [-0·008 to 0·001], treatment effect -0·020 [95% CI -0·039 to -0·009] per year, p=0·0019). Six (5%) participants reached end-stage kidney disease (ie, an eGFR of <15 mL/min per 1·73 m2; three in each group) during the course of the study. The risk difference between treatment groups was 0·02 (95% CI -0·15 to 0·19, p=0·82) for overall adverse events and 0·07 (-0·05 to 0·19, p=0·25) for serious adverse events. Intensive treatment was not associated with worse renal outcomes or greater adverse effects than standard treatment. INTERPRETATION: These results suggest that cardiac remodelling in children with chronic kidney disease is related to blood pressure control and that a target office systolic blood pressure at the 50th percentile is close to the optimal target for preventing increased left ventricular mass. FUNDING: British Heart Foundation.

HNF1B mutations associate with hypomagnesemia and renal magnesium wasting.

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

A fatal case of cerebral oedema with hyponatraemia and massive polyuria after renal transplantation.

We report the case of a child who died from severe cerebral oedema in the context of hyponatraemia and extreme polyuria immediately after renal transplantation. The patient was treated according to a standard post-transplantation protocol, receiving 0.45% saline solution for urine output replacement. The case highlights the dangers of massive fluid therapy in the context of polyuria and, therefore, the need for intensive monitoring.

Bacterial-Fungal Interactions Including Quorum Sensing, Between 2 Opportunistic Pathogens, Resulting in Post-Traumatic Sepsis in a Child Presenting With a Closed Femoral Fracture.

Pseudomonas aeruginosa and Candida albicans (are opportunistic pathogens that cause systemic infections in immune-suppressed patients. They show important bacterial-fungal interactions including quorum sensing. This involves cell signaling to communicate between the cells of their own colony and the cells of rival microbes or the host. It is thought that this phenomenon is vital in the potential competition and virulence of the organisms. We report a case of a previously healthy 2-year-old boy, where an accidental injury had been sustained resulting in a closed fracture of femur. He subsequently developed sepsis related to co-infection by C. albicans and P. aeruginosa. Trauma may result in a transient immune-suppression and predispose to sepsis caused by opportunistic microorganisms. They can engage in bacterial-fungal interaction. Clinicians should consider invasive co-infection when initial cultures show evidence for only 1 pathogen.

Growth and PTH in prepubertal children on long-term dialysis.

Growth failure is an important complication for children on dialysis. One possible influence on growth is renal bone disease. We reviewed the case notes of 35 children (23 boys), mean (range) age at inclusion 2.8 (0.25-8.9) years (17 children age <2 years), on dialysis for 2.0 (1-4.8) years, for growth, PTH, calcium and phosphate levels and medications. Data collection ended at age 10 years, commencement of growth hormone (rhGH) or renal transplantation. The mean (range) height standard deviation score (HtSDS) at the start of dialysis was -2.06 (-5.90 to 0.63). No change in HtSDS per year was observed; the median was -0.06 (-1.07 to 2.39). Children aged <2 years showed catch-up growth in the first year on dialysis; median change in HtSDS was 0.31 (-0.78 to 3.13). Mean plasma calcium and ionised calcium were approximately at the mid-point and phosphate just above the mid-point of the respective normal ranges. The median PTH level was 1.52 times the upper limit of normal and levels did not correlate with growth. Our results indicate that intensive nutritional therapy and phosphorus control aiming to keep PTH within the normal range prevents further loss of HtSDS in short children on dialysis. In some children under 2 years of age catch-up growth can be observed in the first dialysis year.

Lip hypertrophy secondary to cyclosporin treatment.

Gingival hypertrophy is a well-documented side effect of cyclosporin therapy, but severe lip enlargement is less frequently recognised. This can lead to poor body image, low self-esteem and non-compliance, especially in the older childhood and adolescent age groups. We describe two paediatric renal transplant recipients who had marked lip hypertrophy as a consequence of cyclosporin (Neoral) treatment. On changing the immunosuppression to tacrolimus (Prograf), this resolved. We recommend that a change in immunosuppressant therapy be considered in children with significant changes to facial appearance.

Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis.

BACKGROUND: Prognostic factors and outcome are incompletely known in childhood mesangiocapillary glomerulonephritis (MCGN). This study aimed to correlate renal outcome with clinical and histopathological variables. METHODS: We conducted a two-centre retrospective analysis of children with MCGN. RESULTS: Fifty-three children presented at a mean age of 8.8 years (range: 13 months-15 years). They were followed for a median of 3.5 years (range: 0-17 years). Histological classification identified 31 type 1, 14 type 2, two type 3 and six undetermined type. Mean renal survival [time to end-stage renal failure (ESRF)] was projected to be 12.2 years [confidence interval (CI): 9.7-14.6 years]. Five and 10 year renal survival was 92% (CI: 88-100%) and 83% (CI: 74-92%), respectively. Those with nephrotic syndrome at presentation had mean renal survival of 8.9 years (CI: 7.1-10.7 years) vs 13.6 years for those without (CI: 10.8-16.5 years) (P = 0.047). The mean estimated glomerular filtration rate (eGFR) at 1 year in those who progressed to ESRF was 52 vs 98 ml/min/1.73 m2 in those who did not (P < 0.001). Chronic damage scored on the first biopsy in 31 children (one centre) was positively associated with adverse renal outcome at 5 years: <20% was associated with 100% and > or =20% with 71% 5-year renal survival (P = 0.006). In 29 children treated with steroid there was a higher proportion (76%) with reduced eGFR at presentation and a significantly higher incidence of nephrotic syndrome (P = 0.002) and hypertension (P = 0.037). There were no significant differences in outcome eGFR, hypertension or proteinuria. CONCLUSIONS: Nephrotic syndrome at presentation and subnormal eGFR at 1 year were adverse features. The finding that structural disease at onset predicted poor renal outcome at 5 years has implications for the design of therapeutic trials. Treatment of MCGN was variable and not evidence-based.