Jeffrey M. Saland

Masked Hypertension Associates with Left Ventricular Hypertrophy in Children with CKD

Left ventricular hypertrophy (LVH) associates with increased risk for cardiovascular disease. Hypertension leads to LVH in adults, but its role in the pathogenesis of LVH in children is not as well established. To examine left ventricular mass and evaluate factors associated with LVH in children with stages 2 through 4 chronic kidney disease (CKD), we analyzed cross-sectional data from children who had baseline echocardiography (n = 366) and underwent ambulatory BP monitoring (n = 226) as a part of the observational Chronic Kidney Disease in Children (CKiD) cohort study. At baseline, 17% of children had LVH (11% eccentric and 6% concentric) and 9% had concentric remodeling of the left ventricle. On the basis of a combination of ambulatory and casual BP assessment (n = 198), 38% of children had masked hypertension (normal casual but elevated ambulatory BP) and 18% had confirmed hypertension (both elevated casual and ambulatory BP). There was no significant association between LVH and kidney function. LVH was more common in children with either confirmed (34%) or masked (20%) hypertension compared with children with normal casual and ambulatory BP (8%). In multivariable analysis, masked (odds ratio 4.1) and confirmed (odds ratio 4.3) hypertension were the strongest independent predictors of LVH. In conclusion, casual BP measurements alone are insufficient to predict the presence of LVH in children with CKD. The high prevalence of masked hypertension and its association with LVH supports early echocardiography and ambulatory BP monitoring to evaluate cardiovascular risk in children with CKD.

Favorable Long-Term Outcome after Liver-Kidney Transplant for Recurrent Hemolytic Uremic Syndrome Associated with a Factor H Mutation

A male child initially presented with atypical hemolytic uremic syndrome (HUS) at the age of 4 months and progressed within weeks to end stage renal disease (ESRD). At the age of 2 years he received a live‐related kidney transplant from his mother, which, despite initial good function, was lost to recurrent disease after 2 weeks. Complement factor H analysis showed low serum levels and the presence of two mutations on different alleles (c.2918G > A, Cys973Tyr and c.3590T > C, Val1197Ala). His survival on dialysis was at risk because of access failure and recurrent bacteremic episodes. Therefore, at the age of 5 years he received a combined liver‐kidney transplant with pre‐operative plasma exchange. Initial function of both grafts was excellent and this has been maintained for over 2 years. This report suggests that despite setbacks in previous experience, combined liver‐kidney transplantation offers the prospect of a favorable long‐term outcome for patients with HUS associated with complement factor H mutations.

Update on the metabolic syndrome in children

Purpose of review Provides an update on the metabolic syndrome in childhood. Recent findings The metabolic syndrome is increasingly recognized among children. It is nearly exclusively encountered in overweight and obese individuals and is associated with atherosclerosis. Development and clustering of cardiovascular risk factors is influenced by many characteristics including heritable traits, prenatal and infantile influences, diet, physical activity, and socioeconomic status. Summary Epidemiological data have become mature in this area. Efforts to design and implement systems to prevent and treat the metabolic syndrome are required.

Successful Liver-Kidney Transplantation in Two Children With aHUS Caused by a Mutation in Complement Factor H

A 12‐month‐old boy and his 16‐year‐old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver‐kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre‐ and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow‐up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver‐kidney transplantation combined with pre‐ and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

Management of hemolytic uremic syndrome

2011 has been a special year for hemolytic uremic syndrome (HUS): on the one hand, the dramatic epidemic of Shiga toxin producing E. coli -associated HUS in Germany brought the disease to the attention of the general population, on the other hand it has been the year when eculizumab, the first complement blocker available for clinical practice, was demonstrated as the potential new standard of care for atypical HUS. Here we review the therapeutic options presently available for the various forms of hemolytic uremic syndrome and show how recent knowledge has changed the therapeutic approach and prognosis of atypical HUS.

Successful Split Liver-Kidney Transplant for Factor H Associated Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Case report. RESULTS Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr. CONCLUSIONS This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

Lipoprotein metabolism in chronic renal insufficiency.

Chronic renal insufficiency (CRI) is associated with a characteristic dyslipidemia. Findings in children with CRI largely parallel those in adults. Moderate hypertriglyceridemia, increased triglyceride-rich lipoproteins (TRL) and reduced high-density lipoproteins (HDL) are the most usual findings, whereas total and low-density lipoprotein cholesterol (LDL-C) remain normal or modestly increased. Qualitative abnormalities in lipoproteins are common, including small dense LDL, oxidized LDL, and cholesterol-enriched TRL. Measures of lipoprotein lipase and hepatic lipase activity are reduced, and concentrations of apolipoprotein C-III are markedly elevated. Still an active area of research, major pathophysiological mechanisms leading to the dyslipidemia of CRI include insulin resistance and nonnephrotic proteinuria. Sources of variability in the severity of this dyslipidemia include the degree of renal impairment and the modality of dialysis. The benefits of maintaining normal body weight and physical activity extend to those with CRI. In addition to multiple hypolipidemic pharmaceuticals, fish oils are also effective as a triglyceride-lowering agent, and the phosphorous binding agent sevelamer also lowers LDL-C. Emerging classes of hypolipidemic agents and drugs affecting sensitivity to insulin may impact future treatment. Unfortunately, cardiovascular benefit has not been convincingly demonstrated by any trial designed to study adults or children with renal disease. Therefore, it is not possible at this time to endorse general recommendations for the use of any agent to treat dyslipidemia in children with chronic kidney disease.

Carotid Intima-Media Thickness in Children with CKD: Results from the CKiD Study

BACKGROUND AND OBJECTIVES In adults, increased carotid intima-media thickness (cIMT) as assessed by ultrasonography is a valid predictor of cardiovascular events. Children with CKD are known to be at increased cardiovascular risk. This study sought to identify cardiovascular risk factors associated with increased cIMT in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of cIMT obtained after 12 months of follow-up of 101 children aged 2-18 years with mild to moderate CKD (median GFR 42.9 ml/min per 1.73 m(2)) in the Chronic Kidney Disease in Children cohort study enrolled between April 2005 and September 2009 and 97 healthy pediatric controls between January 2003 and December 2008. An average of six standardized B-mode ultrasound measurements constituted the overall cIMT measurement. RESULTS The median cIMT was 0.43 mm (interquartile range, 0.38-0.48) compared with 0.41 mm in healthy controls (P=0.03 for difference). After multivariable adjustment, the median cIMT was 0.02 mm (95% confidence interval [CI], 0.01-0.05) larger than that of the healthy controls. In a multivariable linear regression analysis, dyslipidemia and hypertension were associated with 0.05 mm (95% CI, 0.01-0.08) and 0.04 mm (95% CI, 0.003-0.08) greater mean cIMT, respectively. Body mass index, CKD etiology, GFR, birth weight, pubertal status, calcium, phosphorus, sex, and race were not associated with cIMT. CONCLUSIONS cIMT is significantly elevated among children with CKD, as is the prevalence of other cardiovascular risk factors. Of these risk factors, hypertension and dyslipidemia are significantly associated with increased cIMT.

The prevalence of osteopenia in pediatric renal allograft recipients varies with the method of analysis.

Background:  Pediatric renal allograft recipients often suffer from osteopenia and the potential for increased fractures. Although modern densitometers are widely available, their use in children is complicated by lack of optimal interpretive criteria.

Dyslipidemia in children with chronic kidney disease

Dyslipidemia, a known risk factor for atherosclerosis, is frequent among both adults and children with chronic kidney disease. Here, we describe the prevalence and pattern of dyslipidemia from a cross-sectional analysis of 391 children aged 1-16 years, enrolled in the multicenter Chronic Kidney Disease in Children (CKiD) study, with a median glomerular filtration rate (GFR), measured by the plasma disappearance of iohexol, of 43 ml/min per 1.73 m2. Multivariate analysis was applied to adjust for age, gender, body mass index (BMI), GFR, and the urinary protein/creatinine ratio. Proteinuria was in the nephrotic range in 44 and the BMI exceeded the 95th percentile in 57 patients of this cohort. Baseline lipid analysis found a high prevalence of hypertriglyceridemia in 126, increased non-HDL-C in 62, and reduced HDL-C in 83. Overall, 177 children had dyslipidemia, of whom 79 had combined dyslipidemia. Lower GFR was associated with higher triglycerides, lower HDL-C, and higher non-HDL-C. Nephrotic-range proteinuria was significantly associated with dyslipidemia and combined dyslipidemia. Compared with children with a GFR>50, children with a GFR<30 had significantly increased odds ratios for any dyslipidemia or for combined dyslipidemia. Hence, among children with moderate chronic kidney disease, dyslipidemia is common and is associated with lower GFR, nephrotic proteinuria, and non-renal factors including age and obesity.