J. Brodehl

Reference values for cystatin C serum concentrations in children

Abstract. Cystatin C, a low molecular weight protein, is a new endogenous marker of renal function whose serum concentration correlates better with glomerular filtration rate than creatinine. The aim of the present study was to define a reference interval for cystatin C concentrations in children. Cystatin C was measured by an immunoturbidimetric assay in sera obtained from 258 children (93 girls, 165 boys, median age 6.29 years, range 1 day to 18 years) without evidence of kidney disease. The reference interval was calculated non-parametrically using the 2.5th and 97.5th percentiles. For comparison, creatinine was measured in the same samples. The cystatin C concentration was highest on the first days of life (range 1.64–2.59 mg/l) with a rapid decrease during the first 4 months. Beyond the 1st year, the cystatin C concentration was constant, with a reference interval of 0.7–1.38 mg/l. In contrast, serum creatinine concentrations steadily increased with age until adulthood. Compared with creatinine, cystatin C facilitates the recognition of abnormal renal function in children as its reference range is constant beyond the 1st year of life. The higher levels of cystatin C in the 1st year of life probably reflect the low glomerular filtration rate of neonates and infants.

Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients

OBJECTIVES:Progressive familial intrahepatic cholestasis (PFIC) usually presents with pruritus, jaundice, hepatomegaly, and growth failure. A group of PFIC is recognized by marked elevation of total serum bile acids, decreased serum apolipoprotein A-1, and high-density lipoprotein, but normal γ-glutamyltranspeptidase and cholesterol. Although medical therapy generally fails, partial external biliary diversion (DIV) has been used with promising results for cholestasis. However, little has been reported of its effect on linear growth, synthetic liver function, and lipid metabolism.METHODS:DIV was performed on six noncirrhotic children with PFIC, all suffering from severe pruritus and cholestasis, refractory to medical treatment. Stature was below −1 (median, −2.3) standard deviation score (SDS) for height in all cases. All patients had markedly enhanced bile acids (307 ± 72 μml/L), markedly decreased high-density lipoprotein (20 ± 7 mg/dl), and apolipoprotein A-1 (58 ± 37 mg/dl), but normal γ-glutamyltranspeptidase and cholesterol. In addition, cholinesterase activity, monoethylglycinexylidide test, and Fischers ratio indicated a significantly reduced synthetic liver function in all children but the youngest.RESULTS:After DIV, all patients were consistently relieved of pruritus, and experienced normalization of all liver function tests, including cholinesterase activity, monoethylglycinexylidide test, and Fischers ratio, as well as the serum lipid profile within 1 yr. In addition, a marked catch-up growth (median, +1.3 SDS) was evident after 1 yr in all cases.CONCLUSIONS:This report shows an excellent result of DIV in noncirrhotic PFIC patients and compares favorably with other reports. All patients experienced complete remission, including normalization of synthetic liver function and lipid metabolism. For the first time we have shown that DIV can also be associated with an accelerated growth in these patients.

Oxalate elimination via hemodialysis or peritoneal dialysis in children with chronic renal failure.

Abstract. Oxalate elimination and oxalate dialysance via hemodialysis (HD) or peritoneal dialysis (CAPD) has not been studied in detail in pediatric patients. We studied plasma oxalate, oxalate elimination, and oxalate dialysance in 15 infants and children undergoing CAPD (9 female, 6 male, aged 9 months to 18 years) and in 10 children on HD (4 female, 6 male, aged 7 – 18 years). Two children in each group had primary hyperoxaluria (PH). The mean duration of dialysis prior to examination was 12±11 months in CAPD and 31±23 months in HD patients. Bicarbonate HD was performed 5 h three times a week, CAPD consisted of five daily exchanges in 5 patients and four changes in the remaining 10 children (dwell volume 40 ml/kg body weight, 2.3 g/l glucose). Although oxalate dialysance was significantly higher in HD (mean 115.6 ml/min per 1.73 m2 in HD versus 7.14 ml/min in CAPD), mean oxalate elimination per week was not different between both renal replacement therapies (3,478 μmol/1.73 m2 surface area/week in CAPD versus 3,915 μmol/1.73 m2 per week in HD). Oxalate elimination in patients with PH was between 6,650 and 9,900 μmol/week. Plasma oxalate remained elevated in both procedures [28 – 84 μmol/l in CAPD (92/148 in PH) and 33 – 101 μmol/l in HD (70/93 in PH)]. Oxalate elimination can be increased by a more frequent hemodialysis regimen.

Cyclosporin A in paediatric kidney transplantation.

Cyclosporin A (CyA) is an immunosuppressive agent which has been used in children following kidney transplantation since 1982. The paediatric experience made with CyA in a single centre is reported here. Forty-seven children, ranging in age from 2 to 16 years, were given transplants between September 1982 and May 1986 and received CyA with low-dose prednisolone for immunosuppression. The mean cold ischaemia time of the grafts was 20.9 h. Under routine volume expansion during and 24 h post-transplantation, 40 grafts (85%) functioned immediately. Acute rejection episodes occurred with the highest frequency during the 1st month (0.6 rejection/patient). The actuarial surival rate for patients was 98% after 3 years. Graft survival was 92% after 1 year, 87% after 2 years and 78% after 3 years. The side-effects observed with CyA were hypertrichosis (38%), neurological complications (21%), and infections (17%). One girl of 16 years developed benign mammary fibroadenomas. Hypertension was common (60%), but less so than seen with conventional therapy (83%). Graft function was reduced. The mean creatinine clearance at 6 weeks after transplantation was 60 ml/min per 1.73 m2, after 1 year was 46.4 ml/min per 1.73 m2 and after 2 years it was 42.5 ml/min per 1.73 m2. Twenty-nine children with functioning grafts of at least 1 year could be evaluated for growth performance and normal or even catch-up growth could be demonstrated for the whole group. The individual annual growth rates expressed by standard deviation score (SDS) remained stable or even improved 3 years after kidney transplantation. Longer periods of follow-up are necessary to confirm whether the advantages concerning survival rates and growth rates persist over time and will outweigh the side-effects of CyA treatment.

Regulation of the mitochondrial ATP-synthase in human fibroblasts

The F1F0-ATPase activity of mitochondrial complex V can be rapidly measured in sonicated preparations of monolayer skin fibroblast cultures from children. We show that direct regulation at the level of ATP-synthase occurs in these cell preparations. ATP-synthase capacity is decreased in response to blocking of the respiratory chain by cyanide (mimicking anoxia) or uncoupling of mitochondria. ATP-synthase capacity falls to 60% and 35% of control, respectively. Up-regulation of ATP-synthase can be demonstrated in fibroblasts exposed to 4 mmol/l calcium (127% of control). Mitochondrial recovery was unchanged under the different incubation conditions as judged by the activity of mitochondrial marker enzymes. We conclude that direct regulation at the level of ATP-synthase occurs in vivo in human fibroblasts. The naturally occurring inhibitor protein IF1 and the calcium binding inhibitor protein CaBI may be involved in this regulation of ATP-synthase.

Absence of cytochrome c oxidase activity in a boy with dysfunction of renal tubules, brain and muscle

We report on a boy who developed proximal renal tubular acidosis with loss of carnitine at the age of about 6 months. A few months later he began to suffer from progressive muscular weakness and neurological disturbances. Blood biochemistry showed elevated lactate and β-hydroxybutyrate with increased lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios. A high urinary excretion of lactate and citric acid cycle intermediates was found. These results indicated a defect of the mitochondrial respiratory chain. Analysis of biopsy material from skeletal muscle revealed low activities of all respiratory chain complexes. In muscle and fibroblasts cytochrome c-oxidase (complex IV) was absent. Despite high dose multi-vitamin therapy the boy died at the age of 30 months from central respiratory failure. At autopsy the neuropathological diagnosis of Leigh disease was made.

Paediatric aspects of renal transplantation: experience of a single centre

From 1970 to 1991 a total of 244 renal transplantations were performed in 203 children at the Medical School in Hannover. The mean patient age was 10.4 years with a range between 11 months and 16.9 years. Fifty-nine children received a living donor graft from one parent and 144 received cadaveric grafts. Forty-two children were transplanted without prior dialysis treatment. After 20 years the overall survival rates were 86% for the patients and 39% for the first grafts. Grafts from donors below 5 years of age had a less favourable survival (44% after 5 years). Pre-emptive transplantation yielded comparable results with the benefit of a shorter period of uraemia. Hypertension developed in 80% of transplanted patients. Only children with living related donor grafts had significantly less hypertensive problems independent of the immunosuppressive regimen. Post-transplantational growth improved under cyclosporin. Children with nephropathic cystinosis also showed catch up growth after transplantation under cyclosporin. The long-term outcome and rehabilitation of grown-up recipients were encouraging.