Marc R. Lilien

Early statin therapy restores endothelial function in children with familial hypercholesterolemia

OBJECTIVES This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH). BACKGROUND Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD. METHODS The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment. RESULTS At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05). CONCLUSIONS Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.

Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia

OBJECTIVES in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history. STUDY DESIGN 50 FH children, 10-18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh(+)) and 19 children had no events in the family (fh(-)). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery. RESULTS baseline characteristics were comparable for fh(+), fh(-) and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7+/-4.4 vs. 15.6+/-6.8%, P<0.03). In addition, FMD was significantly lower in fh(+) compared to fh(-) (10.7+/-9.9 vs. 13.3+/-4.6%, P<0.05). CONCLUSION In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease.

Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics

BackgroundMutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).MethodsDifferent mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome.ResultsIn 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ∆CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant.ConclusionsPerforming adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options.

Increased Arterial Stiffness in Young Adults with End-Stage Renal Disease since Childhood

Increased arterial stiffness is a risk factor for mortality in adults over 40 yr of age with end-stage renal disease (ESRD). As no data exist on vascular changes in young adults with ESRD since childhood, a long-term outcome study was performed. All living Dutch adult patients with onset of ESRD between 1972 and 1992 at age 0 to 14 yr were invited for carotid artery and cardiac ultrasound and BP measurements. Data on clinical characteristics were collected by review of all medical charts. Carotid ultrasound data were compared with those of 48 age-matched and gender-matched healthy controls. Carotid artery and cardiac ultrasound was performed in 130 out of 187 eligible patients. Mean age was 29.0 (20.7 to 40.6) yr. Compared with controls, patients had a similar intima media thickness but a reduced mean arterial wall distensibility DC (40.0 versus 45.0 kPa(-1). 10(-3); 95% CI, -9.1 to -0.8; P < 0.001), an increased stiffness parameter beta (4.2 versus 3.8; 95% CI, 0.05 to 0.68; P = 0.02), an increased elastic incremental modulus E(inc) (0.35 versus 0.27 kPa. 10(3); 95% CI, 0.02 to 0.12; P < 0.001). Multiple regression analyses in all subjects revealed that ESRD was associated with an increase in beta and E(inc). Arterial wall properties of patients currently on dialysis and transplanted patients were comparable. In all patients, current systolic hypertension was associated with increased E(inc) and decreased DC. In conclusion, carotid arterial wall stiffness is increased in young adult patients with pediatric ESRD. Hypertension is a main determinant and might be a target for treatment of these potentially lethal arterial wall changes.

Cardiovascular disease as a late complication of end-stage renal disease in children

As in older adults, cardiovascular disease is the most important cause of death in adolescents and young adult patients with end-stage renal disease (ESRD) since childhood. This concerns patients on dialysis as well as transplant patients, despite the fact that a long duration of dialysis during childhood is an extra mortality risk factor. Left ventricular hypertrophy (LVH), aortic valve calcification, and increased arterial stiffness, but not increased arterial intima media thickening, are the most frequently observed alterations in young adult survivors with childhood ESRD. In transplanted patients a concentric LVH as a result of chronic hypertension is mostly observed; in dialysis patients a more asymmetric septal LVH is found as a result of chronic volume overload. These results suggest that in children and young adults with ESRD chronic pressure and volume overload, a high calcium-phosphate product, and chronic inflammation, but not dyslipidemia, play a role in the development of cardiovascular disease.

Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency

Abstract Several prospective trials have shown that recombinant human growth hormone (GH) accelerates growth significantly during the first years of therapy, but the effects of long-term GH therapy with regard to long-term growth response and safety have not yet been established. Forty-five Dutch prepubertal children [28 boys, 17 girls, mean (SD) age 7.8 (3.4) years] with chronic renal insufficiency (CRI) and severe growth retardation started GH therapy between 1988 and 1991 within one of the randomized Dutch trials. Long-term GH therapy, in this study a maximum of 8 years, resulted in a sustained and significant improvement of height standard deviation score (SDS) compared with baseline values (P<0.001). The mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of GH therapy. During the following years the mean height SDS gradually increased, thereby approaching the mean target height SDS after 6 years of GH therapy. Three factors were significantly associated with the height SDS after 4 years of GH therapy: height SDS at the start (+) of therapy, age at the start of therapy (-), and the duration of dialysis treatment (-). Bone maturation did not accelerate during long-term GH therapy. Children on a conservative regimen at the start of GH therapy had no accelerated deterioration of renal function during 6 years of GH therapy. The average daily GH dose administered over the years had no significant influence on the glomerular filtration rate after 4 years. GH therapy had no adverse effects or significant effect on parathyroid hormone concentration, nor were there any radiological signs of renal osteodystrophy. Puberty started at a median age, within the normal range, of 12.4 years in boys and 12.0 years in girls, respectively. Long-term GH therapy leads to a sustained improvement in height SDS in children with growth retardation secondary to CRI, resulting in a normalization of height in accordance with their target height SDS, without evidence of deleterious effects on renal function or bone maturation. A GH dosage of 4 IU/m2 per day appears efficient and safe. Our long-term data show that final height will be within the normal target height range when GH therapy is continued for many years.

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin α3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional α3β1, causing a fatal multiorgan disorder.

Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis

BACKGROUND Focal segmental glomerulosclerosis (FSGS) is a major cause of steroid-resistant nephrotic syndrome in childhood with a central role for the podocytes in the pathogenesis. Mutated proteins expressed in podocytes cause proteinuria. The role of combined gene defects in the development of FSGS is less clear. METHODS We analysed seven podocyte genes known to cause proteinuria and FSGS in a group of 19 non-familial childhood-onset steroid-resistant FSGS patients. These genes include NPHS1, NPHS2, ACTN4, CD2AP, WT-1, TRPC6 and PLCE1. We also screened for the mitochondrial A3243G DNA transition associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and occasionally FSGS. RESULTS No mutations were found in the ACTN4 and TRPC6 genes, and no mitochondrial A3243G DNA transition was found in our group of patients. Two patients showed mutations in the CD2AP gene, one combined with an NPHS2 mutation. A tri-allelic hit was found in a patient carrying compound heterozygous NPHS2 mutations and a heterozygous NPHS1 mutation. In another patient a de novo WT-1 mutation was found combined with a heterozygous NPHS1 mutation, and finally two patients showed three heterozygous PLCE1 mutations. CONCLUSIONS In our rather small group of 19 steroid-resistant FSGS patients, we found 11 mutations in podocyte genes in 6 patients. In four of them the found mutations could explain the pathology. Our data suggest that combined gene defects in podocyte genes may play a role in the development of FSGS.

Cardiovascular disease in children with CKD or ESRD.

Cardiovascular disease accounts for 40% of all deaths among pediatric patients with end-stage renal disease (ESRD). ESRD has a particularly large influence on the cardiovascular system in children, as indicated by the more than 700-fold increased risk of cardiac death in affected individuals compared with healthy children of the same age. The prevalence of ESRD is low in children, however, and, consequently, few cardiac deaths occur. As a result, prospective follow-up studies of cardiac risk factors in the pediatric setting are lacking. Nevertheless, cross-sectional data on cardiac disease in children with ESRD have started to emerge. Arterial medial calcification is more prominent in children than classic atherosclerotic intimal calcification. Current data suggest that endothelial dysfunction appears early in renal failure in children, and is followed by arterial medial calcification. This calcification causes arterial wall stiffening and subsequently left ventricular hypertrophy. High systolic blood pressure and serum concentrations of intact parathyroid hormone, calcium and phosphate, as well as long-term dialysis, seem to be important risk factors for cardiovascular disease in pediatric patients with ESRD. These features are important targets for preventive intervention. This Review summarizes the currently available data on cardiovascular disease in children with renal failure.

Long-term Follow-up of Renal Transplantation in Children: A Dutch Cohort Study

Background. Few data exist on long-term morbidity, overall survival, and graft survival of pediatric renal transplantation. Methods. The authors performed a long-term cohort study in all Dutch patients, born before 1979, with onset of end-stage renal disease (ESRD) between 1972 and 1992 at age 0 to 15 years. Data on graft survival and determinants of outcome were obtained by reviewing all medical charts. The health status was assessed by cross-sectional examination of surviving patients. Results. Three hundred ninety-seven transplantations were performed in 231 of all 249 patients, of whom 25 died with a functioning graft. Cardiovascular disease was the most prominent cause of death. Graft survival estimates for all transplantations were 59.2%, 45.3%, 35.4%, and 30.3% at 5, 10, 15, and 20 years, respectively. In comparison with azathioprine, cyclosporine as the immunosuppressant was associated with increased graft survival in retransplantations but not in first transplantations. Cross-sectional examination was performed on 110 patients. In 44 patients, the most recent graft survival exceeded 15 years. Co-morbidity was found in 40% of all patients; motor, hearing, or visual disabilities were found in 19%. Bone disease, headaches, itching, and tremors were the most reported disabling problems. Cyclosporine use was associated with hypertension and a history of epilepsy. Compared with all age-matched Dutch inhabitants, the educational attainment was low, and unemployment and parental dependency were high. Conclusions. The authors’ results emphasize the need for reducing cardiovascular disease and metabolic bone disease in pediatric ESRD, a policy toward less toxic antirejection therapy, a more strict treatment of hypertension, and more attention for schooling and social development toward independence.