Salim Caliskan

Strict blood-pressure control and progression of renal failure in children.

BACKGROUND Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

The Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study: Objectives, Design, and Methodology

BACKGROUND AND OBJECTIVES Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. A systemic arteriopathy and cardiomyopathy has been characterized in pediatric dialysis patients by the presence of morphologic and functional abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Comorbidity in Children with CKD (4C) Study is a multicenter, prospective, observational study aiming to recruit more than 600 children, aged 6 to 17 years, with initial GFR of 10 to 45 ml/min per 1.73 m(2). The prevalence, degree, and progression of cardiovascular comorbidity as well as its association with CKD progression will be explored through longitudinal follow-up. The morphology and function of the heart and large arteries will be monitored by sensitive noninvasive methods and compared with aged-matched healthy controls. Multiple clinical, anthropometric, biochemical, and pharmacologic risk factors will be monitored prospectively and related to the cardiovascular status. A whole-genome association study will be performed to identify common genetic variants associated with progression of cardiovascular alterations and/or renal failure. Monitoring will be continued as patients reach end-stage renal disease and undergo different renal replacement therapies. RESULTS While cardiovascular morbidity in adults is related to older age and additional risk factor load (e.g., diabetes), the role of CKD-specific factors in the initiation and progression of cardiac and vascular disease are likely to be characterized with greater sensitivity in the pediatric age group. CONCLUSIONS The 4C study is expected to provide innovative insight into cardiovascular and renal disease progression in CKD.

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Reduced Systolic Myocardial Function in Children with Chronic Renal Insufficiency

Increased left ventricular (LV) mass in children with chronic renal insufficiency (CRI) might be adaptive to sustain myocardial performance in the presence of increased loading conditions. It was hypothesized that in children with CRI, LV systolic function is impaired despite increased LV mass (LVM). Standard echocardiograms were obtained in 130 predialysis children who were aged 3 to 18 yr (59% boys) and had stages II through IV chronic kidney disease and in 130 healthy children of similar age, gender distribution, and body build. Systolic function was assessed by measurement of fractional shortening at the endocardial (eS) and midwall (mS) levels and computation of end-systolic stress (myocardial afterload). The patients with CRI exhibited a 6% lower eS (33.1 +/- 5.5 versus 35.3 +/- 6.1%; P < 0.05) and 10% lower mS (17.8 +/- 3.1 versus 19.7 +/- 2.7%; P < 0.001) than control subjects in the presence of significantly elevated BP, increased LVM, and more concentric LV geometry. Whereas the decreased eS was explained entirely by augmented end-systolic stress, mS remained reduced after correction for myocardial afterload. The prevalence of subclinical systolic dysfunction as defined by impaired mS was more than five-fold higher in patients with CRI compared with control subjects (24.6 versus 4.5%; P < 0.001). Systolic dysfunction was most common (48%) in patients with concentric hypertrophy and associated with lower hemoglobin levels. CRI in children is associated with impaired intrinsic LV contractility, which parallels increased LVM.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

A Child With Primary Sjögren Syndrome and a Review of the Literature

Primary Sjögren syndrome (pSS) is an uncommon disease in childhood. Childhood pSS might have different clinical manifestations than adult pSS. We describe a 13-year-old girl with multiple episodes of bilateral parotid swelling lasting 2 years. Her history included severe arthralgia, local edema, and purpura episodes since 9 years of age. During her 3-week hospitalization, 2 episodes of parotid swelling occurred, which both resolved in 48 hours. Ultrasonography and magnetic resonance images of parotid glands showed parenchymal inhomogeneity related to adipose degeneration and nodular pattern. Investigations showed elevated erythrocyte sedimentation rate, the presence of hypergammaglobulinemia, positive antinuclear antibody, and elevated rheumatoid factor, anti—Sjögren syndrome antigen A, and anti—Sjögren syndrome antigen B. Histopathologic examination of labial minor salivary glands revealed focal periductal lymphocytic infiltrate and sialoduct ectasia. She was diagnosed as having pSS. Recurrent parotid swelling is a more characteristic feature of disease in children, and this finding should alert the clinician to the possible diagnosis of pSS.

Traditional and “new” cardiovascular risk markers and factors in pediatric dialysis patients

Cardiovascular disease (CVD) is the principal cause of mortality in patients with end-stage renal disease (ESRD). The aim of this study was to analyze carotid intima-media thickness (cIMT), endothelium-dependent dilatation (EDD), and left ventricular mass index (LVMI) as the cardiovascular risk markers and to investigate the independent risk factors of these markers in pediatric dialysis patients. This study included 39 children and adolescents undergoing dialysis (15 hemodialysis and 24 peritoneal dialysis) and 15 age- and gender-matched healthy subjects. The cIMT and EDD were assessed by high-resolution ultrasound, and LVMI was calculated from standard echocardiographic measurements. Compared with control subjects, cIMT standard deviation scores (SDS), LVMI, total homocysteine (tHcy), and high-sensitivity C-reactive protein (hs-CRP) values were significantly higher in patients, but EDD values did not differ. The mean hs-CRP level was significantly higher in hemodialysis (HD) patients than in peritoneal dialysis (PD) patients. The cIMT-SDS and LVMI were associated with several variables in univariate analysis. Stepwise linear regression analysis, indexed SBP (p = 0.017), and hemoglobin (p = 0.001) turned out to be independent variables for predicting LVMI, and a significant predictor of cIMT was indexed diastolic blood pressure (DBP) (p = 0.035). The causes of atherosclerosis and left ventricular hypertrophy are multifactorial in children and adolescents with ESRD. Better management of hypertension and anemia may be priorities for preventing or improving CVD in these patients.

Haemoperfusion in Amanita phalloides Poisoning

Amanita phalloides is responsible for about 90 per cent of all fatal cases of mushroom intoxication. The amatoxins, the main toxic component of these fungi, are responsible for gastro-intestinal symptoms as well as hepatic and renal failure. Three brothers with Amanita phalloides poisoning were admitted with gastro-intestinal symptoms beginning 12 h after ingestion. Jaundice, hepatomegaly and neurological symptoms were not present, but liver enzymes were moderately increased. Alfa-amanitin was detected in sera of all patients. All patients underwent charcoal hemoperfusion and two of them had additional hemodialysis along with conservative therapy. Liver enzymes that showed a marked increase on the second day of therapy decreased to normal levels on the 28th day. All of our patients survived. This life saving role of early haemoperfusion in Amanita phalloides poisoning is emphasized.

Urinary N-acetyl-β-D-glucosaminidase and β2-microglobulin excretion in primary nephrotic children

Enzymuria and low molecular weight proteinuria reflect tubular damage and dysfunction, respectively. We examined urinary N-acetyl-β-. D -glucosamini-dase (U-NAG) and β2-mic

Cardiovascular Phenotypes in Children with CKD: The 4C Study

BACKGROUND AND OBJECTIVES Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m2. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. RESULTS A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. CONCLUSIONS The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.