Predictors of renal replacement therapy and mortality in children with chronic kidney disease

Objectives:

To study the epidemiology of chronic kidney disease (CKD) in children, and to look for risk factors to predict renal replacement therapy (RRT) and mortality.

Methods:

This is a retrospective cohort study conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between 2006 and 2014, where the files of 1,000 children with CKD were reviewed. We determined the effect of consanguinity and hypertension, and being a Saudi indigene on mortality and RRT. We compared children with congenital versus non-congenital causes of CKD.

Results:

The mean±standard deviation age at presentation was 4.9±4.3 years. The median duration of follow up was 1.5 (interquartile range [IQR]: 0.4-4.0) years. Only 9.7% of children received RRT, and 8.3% died. The underlying etiology for CKD was congenital in 537 children. The congenital CKD group presented at a younger age group (3.5±4.0 versus 6.6±3.9 years, p<0.0001), had more advanced stages of CKD (p<0.0001), higher rates of consanguinity (75.4% versus 47.1%, p<0.0001), and RRT (p<0.004) than children with non-congenital CKD. Risk factors for RRT among children with CKD include being a Saudi indigene (relative risk [RR]=1.49, 95% confidence interval (CI): 1.01-2.21), and hypertensive (RR=5.29, 95% CI: 3.54-7.91). The risk factor for mortality was hypertension (RR=2.46, 95% CI: 1.66-3.65).

Conclusion:

Congenital causes of CKD represent the main etiology of CKD in children living in the western province of Saudi Arabia. Significant risk factors for RRT include congenital CKD, Saudi nationality, and hypertension. Hypertension is also a predictor of mortality in children with CKD.Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months with implications for health.1 Children with CKD who are on renal replacement therapy (RRT) have higher mortality rate, which is at least 30-fold higher than their age-matched peers.2 Epidemiological information on the incidence and prevalence of pediatric CKD in children is currently limited,3 particularly in developing countries. Furthermore, most of the available epidemiological data are from end-stage kidney disease (ESKD) registries, and information on the earlier stages of pediatric CKD is still lacking.4 The early stages of CKD in the pediatric population are in most cases asymptomatic, and are therefore under-diagnosed and under-reported.4 Direct comparisons of the incidence and prevalence rate of pediatric CKD are complex since each pediatric CKD registries uses different definition; some depend on the estimated glomerular filtration rate (eGFR), while others use serum creatinine levels. The incidence in Europe was consistent between 11-12 per million of the age-related population (pmarp) for CKD stages 3-5, and 8 pmarp for CKD stages 4-5.4 Data available on the exact prevalence of various kidney diseases in the Arab world is very limited. Most of the data come from small studies and are of limited generalizability.5 In Kuwait, the mean incidence was found to be as high as 38 pmarp, while the prevalence was as also high at 329 pmarp in 2003.6 An incidence of 11 pmarp and a prevalence of 51 pmarp has been reported in Jordanian children.7 The epidemiological data of CKD in children is very scarce in Saudi Arabia. One study from Asir reported that the mean annual incidence of CRF of 15.6 per million children, the mean annual incidence of ESRF is 9.2 per million children, and congenital anomalies of the urinary system constitute the most common cause of chronic renal failure (CRF).8 Another study from Jeddah reported similar results.9 All these studies enrolled a small number of children (less that 100). In the light of a limited data available regarding the epidemiology of CKD in children in Saudi Arabia, we performed a retrospective study to examine the risk factors for RRT and mortality among children with CKD.     

How to use ECG for decision support in the catheterization laboratory. Cases with inferior ST elevation myocardial infarction

Treatment of acute myocardial infarction has changed considerably during the last few years with the introduction of primary coronary angioplasty. In the acute phase risk stratification is largely based on simple clinical parameters, laboratory markers of myocardial injury and 12-lead electrocardiography. The electrocardiogram is of crucial importance especially during the first few hours after initiation of chest pain when important therapeutic decisions are made. Biochemical markers of myocardial injury are usually not elevated at that time point. Cases with inferior ST-elevation myocardial infarction from our hospital are presented to show how anatomical interpretation of ECG recorded during chest pain helps to risk stratify patients.     

BRAF and NRAS Mutations Are Frequent in Nodular Melanoma but Are not Associated with Tumor Cell Proliferation or Patient Survival

Previous studies have shown frequent mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) or NRAS (neuroblastoma RAS viral [V-ras] oncogene homolog) genes in cutaneous melanoma, but the relationship between these alterations and tumor cell proliferation has not been examined in human melanoma. In our study of 51 primary nodular melanomas and 18 paired metastases, we found mutations in BRAF (codon 600, previously denoted 599) in 15 primary tumors (29%) and eight metastases (44%). The figures for NRAS mutations were 27% and 22%, respectively. Mutations in BRAF and NRAS genes were mutually exclusive in all but one case, and were maintained from primary tumors through their metastases. Mutations, however, were not associated with tumor cell proliferation by Ki-67 expression, tumor thickness, microvessel density, or vascular invasion, and there were no differences in patient survival. Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma.     

Patients’ assessments of the continuity of primary care in Finland: a 15-year follow-up questionnaire survey

Background

Continuity of care is an essential aspect of quality in general practice. This study is the first systematic follow-up of Finnish primary care patients’ assessments with regard to personal continuity of care.

Aim

To ascertain whether patient-reported longitudinal personal continuity of care is related to patient characteristics and their consultation experiences, and how this had changed over the study period.

Design and setting

A 15-year follow-up questionnaire survey that took place at Tampere University Hospital catchment area, Finland.

Method

The survey was conducted among patients attending health centres in the Tampere University Hospital catchment area from 1998 until 2013. From a sample of 363 464 patients, a total of 157 549 responded. The responses of patients who had visited a doctor during the survey weeks (n = 97 468) were analysed. Continuity of care was assessed by asking the question: ‘When visiting the health centre, do you usually see the same doctor?’; patients could answer ‘yes’ or ‘no’.

Results

Approximately half of the responders had met the same doctor when visiting the healthcare centre. Personal continuity of care decreased by 15 percentage points (from 66% to 51%) during the study years. The sense of continuity was linked to several patients’ experiences of the consultation. The most prominent factor contributing to the sense of continuity of care was having a doctor who was specifically appointed (odds ratio 7.28, 95% confidence interval = 6.65 to 7.96).

Conclusion

Continuity of care was proven to enhance the experienced quality of primary care. Patients felt that continuity of care was best realised when they could consult a doctor who had been specifically appointed to them. Despite efforts of the authorities, over the past 15 years patient-reported continuity of care has declined in Finland.     

Effective Variant Detection by Targeted Deep Sequencing of DNA Pools: An Example from Parkinson's Disease

Next‐generation sequencing technologies will dominate the next phase of discoveries in human genetics, but considerable costs may still represent a limitation for studies involving large sample sets. Targeted capture of genomic regions may be combined with deep sequencing of DNA pools to efficiently screen sample cohorts for disease‐relevant mutations. We designed a 200 kb HaloPlex kit for PCR‐based capture of all coding exons in 71 genes relevant to Parkinson's disease and other neurodegenerative disorders. DNA from 387 patients with Parkinson's disease was combined into 39 pools, each representing 10 individuals, before library preparation with barcoding and Illumina sequencing. In this study, we focused the analysis on six genes implicated in Mendelian Parkinson's disease, emphasizing quality metrics and evaluation of the method, including validation of variants against individual genotyping and Sanger sequencing. Our data showed 97% sensitivity to detect a single nonreference allele in pools, rising to 100% where pools achieved sequence depth above 80x for the relevant position. Pooled sequencing detected 18 rare nonsynonymous variants, of which 17 were validated by independent methods, corresponding to a specificity of 94%. We argue that this design represents an effective and reliable approach with possible applications for both complex and Mendelian genetics.     

Expression of an anti‐RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN‐I expression

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of antinucleic acid autoantibodies, high levels of circulating type I interferon (IFN‐I), and an IFN‐I‐dependent elevated expression of activating FcγR. Increases in neutrophils and monocytes are often observed in clinical SLE, but how these contribute to autoantibody and IFN‐I production is poorly understood. Here, we analyzed SLE pathogenesis in 564Igi mice, an SLE‐model strain carrying gene‐targeted heavy and light chain antibody genes encoding an anti‐RNA autoantibody in a C57BL/6 background. Similar to human SLE patients, 564Igi mice produce anti‐RNA autoantibodies and expanded neutrophil and monocyte populations. These myeloid cells produced IFN‐I and exhibit increased FcγRIV expression induced via an IFN‐I autocrine loop. A direct effect of IFN‐I on 564Igi BM B cells and neutrophils was supported by their upregulation of “IFN‐I signature genes”. In addition, 564Igi developing B cells showed upregulated TLR7 resulting in IgG2a/2b class switch recombination and autoantibody production. Our results indicate that the production of anti‐RNA autoantibody is sufficient to induce an increase of BM, blood, and spleen IFN‐I‐producing neutrophils, and suggest a mechanism by which autoantibody and IFN‐I contribute to SLE by activating B lymphocytes, neutrophils, and monocyte effector cells in vivo.     

High frequency of BRAF V600E mutations in ameloblastoma

Ameloblastoma is a benign but locally infiltrative odontogenic neoplasm. Although ameloblastomas rarely metastasise, recurrences together with radical surgery often result in facial deformity and significant morbidity. Development of non‐invasive therapies has been precluded by a lack of understanding of the molecular background of ameloblastoma pathogenesis. When addressing the role of ERBB receptors as potential new targets for ameloblastoma, we discovered significant EGFR over‐expression in clinical samples using real‐time RT–PCR, but observed variable sensitivity of novel primary ameloblastoma cells to EGFR‐targeted drugs in vitro. In the quest for mutations downstream of EGFR that could explain this apparent discrepancy, Sanger sequencing revealed an oncogenic BRAF V600E mutation in the cell line resistant to EGFR inhibition. Further analysis of the clinical samples by Sanger sequencing and BRAF V600E‐specific immunohistochemistry demonstrated a high frequency of BRAF V600E mutations (15 of 24 samples, 63%). These data provide novel insight into the poorly understood molecular pathogenesis of ameloblastoma and offer a rationale to test drugs targeting EGFR or mutant BRAF as novel therapies for ameloblastoma. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk     

Social Impact of Dialysis on Children and Their Families

Objectives

To evaluate the social consequences of dialysis on children and their parents.

Methods

From January through June 2012 short structured interviews with parents or caregivers of children on peritoneal dialysis (PD) or hemodialysis (HD) who were followed up at King Abdulaziz University Hospital, King Faisal Specialty Hospital and Research Center, or the Kidney Center at King Fahad Hospital were conducted. Data were analyzed using the Statistical Package for the Social Sciences.

Results

Thirty six children (22 boys and 16 girls) and their families were included. The mean (SD) age of the children was 11.5?±?6.87 y, and the mean (SD) duration of dialysis was 28?±?11.32 mo. Only one third of the families had the opportunity to choose the modality of dialysis. Both modalities of dialysis had a negative effect on fathers’ jobs in over 50 % of the cases. Similarly, both modalities of treatment had a considerable impact on the quality of care provided by the mothers to other family members. There was no difference between the two modalities on the frequency of admissions.

Conclusions

Both PD and HD had a negative impact on fathers’ jobs and on the level of care provided by mothers to the rest of the family.