Marjatta Antikainen

Management of congenital nephrotic syndrome of the Finnish type

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessively inherited disease characterised by intrauterine onset of massive urinary loss of proteins, 90% of which is albumin. The CNF gene has been localised to the long arm of chromosome 19, but the pathogenesis remains unclear. Historically, all CNF patients died, usually within the first 6 months of life. Today, a normal life can be achieved for a child with CNF by correcting the protein deficiency and normalising nutrition. This is accomplished by early intravenous albumin supplementation, nutritional support, aggressive treatment of complications and early renal transplantation, after bilateral nephrectomy and peritoneal dialysis. In the present article current treatment strategies are reviewed, and our own experience with 43 CNF patients during the last 10 years is presented.

Hepatic Lipase Gene Polymorphisms Influence Plasma HDL Levels Results From Finnish EARS Participants

Hepatic lipase (HL), a triglyceride lipase found in liver, adrenals, testes, and ovaries, takes part in the uptake, remodeling, and function of lipoproteins including HDL, as well as VLDL and chylomicrons. In the present study, the genotype distribution of five HL polymorphisms (-C480T, V133V, T202T, L334F, T457T) and their association to plasma lipid values were investigated. The study participants included 92 students with paternal history of myocardial infarction before the age of 55 and 194 matched control subjects, ie, the Finnish participants of the European Atherosclerosis Research Study (EARS). The allele T of the HL polymorphism -C480T showed an association with elevated HDL, apoA-I, and LpA-I values (ANOVA P < .01). No difference in genotype distribution was observed in the offspring with and without paternal history of myocardial infarction.

Pharmacokinetics and Pharmacodynamics of Pravastatin in Pediatric and Adolescent Cardiac Transplant Recipients on a Regimen of Triple Immunosuppression

In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long‐term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single‐dose pharmacokinetics and short‐term safety of pravastatin in children undergoing regular triple‐drug immunosuppressive therapy after cardiac transplantation.

Phenotype expression in familial combined hyperlipidemia

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

No Evidence of Linkage Between Familial Combined Hyperlipidemia and Genes Encoding Lipolytic Enzymes in Finnish Families

Familial combined hyperlipidemia (FCHL) is characterized by different lipid phenotypes (IIa, IIb, IV) and elevated apolipoprotein B (apo B) levels in affected family members. Despite intensive research, the genes involved in the expression of this complex disorder have not been identified, probably because of problems associated with phenotype definition, unknown mode of inheritance, and most probably genetic heterogeneity. To explore the genetics of FCHL in the genetically homogeneous Finnish population, we collected 14 well-documented Finnish pedigrees with premature coronary heart disease and FCHL-like dyslipidemia. The lipolytic enzymes lipoprotein lipase (LPL), hepatic lipase (HL), and hormone-sensitive lipase (HSL) were selected as initial candidate genes because of their central roles in apo B and triglyceride metabolism. On the basis of the pedigree structures, a dominant mode of inheritance was adopted for linkage analyses, and serum total cholesterol and/or triglyceride levels exceeding the 90th percentile level were set as diagnostic criteria (criterion 1). In pairwise linkage analyses with intragenic markers, no evidence for linkage was found. Instead, the significantly negative LOD scores suggested exclusion of all three loci for single major gene effect. LOD scores were -14.63, -5.03, and -5.70 for the three LPL polymorphisms (theta=0.00); -9.40, -6.30, and -4.74 for the three HL polymorphisms (theta=0.00); and -15.29 for the HSL polymorphism (theta=0.00). The results were very similar when apo B levels over the 90th percentile were used as criteria for affected status (criterion 2). Also, when linkage calculations were carried out using an intermediate or recessive mode of inheritance, the results of pairwise linkage analysis remained negative. Furthermore, when haplotypes were constructed from multiple polymorphisms of the LPL and HL genes, no segregation with the FCHL phenotype could be observed in the 14 Finnish families. Data obtained by the affected sib-pair method supported these findings, suggesting that the LPL, HL, or HSL genes do not represent major loci influencing the expression of the FCHL phenotype.

Growth after renal transplantation in infancy or early childhood.

Abstract Forty-one children <5 years of age at kidney transplantation (TX) were investigated for growth, bone age, and renal function up to 7 years (n=26) after TX. All children received triple immunosuppression, including alternate-day corticosteroid treatment. Catch-up growth was seen in 81% of 30 children without growth hormone (GH) treatment. Children <2 years of age without GH had a mean height standard deviation score (hSDS) of –1.1±0.8 at TX and –1.1±0.5 at 7 years; children between 2 and 5 years improved their hSDS from –1.9±0.9 to –0.4±0.8 (P<0.0001). The hSDS at TX correlated inversely with the ΔhSDS from TX to 7 years (r=–0.80, P=0.0002). Glomerular filtrations rate (GFR) at 5 years post TX correlated with the subsequent growth rate from 5 to 7 years TX (r=0.58, P=0.01). Catch-up growth was seen in all 11 children receiving GH. Their mean hSDS improved from –2.5±0.9 to –1.1±0.9 (P<0.0001). In the majority of children receiving a kidney graft in early life, triple immunosuppression with alternate-day steroids can ensure catch-up growth. In children <5 years of age at TX, growth is predicted better by the degree of stunting than by age.

Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia

Pravastatin is a widely used statin in adults, but its pharmacokinetics in children is not known. Our aim was to determine the single‐dose pharmacokinetics and the lipid‐lowering effect and safety of short‐term administration of pravastatin in children.

The Asn-291-->Ser and Ser-477-->Stop mutations of the lipoprotein lipase gene and their significance for lipid metabolism in patients with hypertriglyceridaemia.

We examined 99 Finnish patients whose serum fasting triglycerides (TG) had exceeded 6.0 mmol L−1, with special interest to their lipid, lipoprotein and post‐heparin plasma lipase activities. The control group consisted of 75 healthy individuals. We also determined the frequency of the Asn‐291→Ser and Ser‐447→Stop mutations both in hypertriglyceridaemic (HTG) subjects and in control subjects. A total of 51 of the original 99 hypertriglyceridaemic patients still had TG > 6.0 mmol L−1 when measured a second time. They are referred to as persistently hypertriglyceridaemic subjects (pHTG). The remaining 48 subjects had TG < 6.0 mmol L−1 in the second measurement and are referred to as sporadically hypertriglyceridaemic subjects (sHTG). The allelic frequencies of the Ser‐447→Stop mutation in the total HTG and sHTG groups were similar to the frequencies present in the control group, but lower in pHTG patients compared with the control group (0.049 vs. 0.153, χ2 = 6.63, P < 0.05). The Asn‐291→Ser mutation was more frequent in HTG group than in the control group (0.0606 vs. 0.013, χ2 = 4.86, P < 0.05). This difference was due to the higher frequency of the minor allele of Asn‐291→Ser in the cohort with persistent hypertriglyceridaemia compared with the control group (0.088 vs. 0.013, χ2 = 8.00, P < 0.01 ). The highest frequency (0.114) of the minor allele of Asn‐291→Ser was found in type 2 diabetic patients with persistent hypertriglyceridaemia. The carrier status of Asn‐291→Ser or Ser‐447→Stop did not predict either post‐heparin plasma lipoprotein lipase (LPL) activities or lipid and lipoprotein levels in any of the groups studied. Our data suggest that overproduction of very low‐density lipoproteins (VLDL) is a more important cause of hypertriglyceridaemia in the Finns than is the LPL deficiency.

Protein and lipid metabolism in nephrotic infants on peritoneal dialysis after nephrectomy

Congenital nephrotic syndrome of the Finnish type (CNF) is associated with protein deficiency despite substantial protein supplementation in the nephrotic state before nephrectomy. Different protein intakes (2.5 vs. 3.7 g/kg per day) in hypoproteinaemic children on continuous cycling peritoneal dialysis (CCPD) were studied. Lipids were also measured to determine whether severe atherogenic abnormalities seen during nephrosis improved after nephrectomy. Growth was normal or became normal with both protein intakes. Serum pre-albumin and transferrin concentrations became normal. Total protein (57±3.0 vs. reference limits 60–75 g/l) and albumin (28±5.0 vs. reference limits 30–50 g/l) concentrations improved but remained below normal, even with the higher protein intake. Muscle mass determined by measuring femoral quadriceps muscle thickness using ultrasound was markedly reduced in all patients at nephrectomy. It improved (P<0.05) in all but 2 patients who had several bacterial infections, but reached normal level in only 3 patients within 6 months. Plasma total, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) triglyceride concentrations decreased (P<0.05,P<0.05 andP<0.01, respectively) and VLDL, LDL and high-density lipoprotein (HDL) particles contained less triglyceride than in the nephrotic state. HDL cholesterol concentrations increased by 28% [0.58±0.22 mmol/l during nephrosis, 0.81±0.21 mmol/l on CCPD after nephrectomy (P<0.05)] but remained below the level of 1.38±0.75 mmol/l in normal controls (P<0.001). If compared with controls there were still significant abnormalities in lipoprotein concentrations on CCPD. Hence, a protein intake of 2.5 g/kg per day representing 140% of the recommended dietary allowance is sufficient to maintain normal growth and improve nutritional and protein status in CNF patients on CCPD. Although lipid levels improved they remained abnormal.

Factors limiting the erythropoietin response in rapidly growing infants with congenital nephrosis on a peritoneal dialysis regimen after nephrectomy

To prevent anemia in seven small children with congenital nephrotic syndrome of the Finnish type (age range 1 to 4 years), we gave recombinant human erythropoietin in a dose up to 150 IU/kg/per week. We then studied the limiting factors during 14 weeks. On a peritoneal dialysis regimen after nephrectomy, the patients grew considerably (range +0.1 to 2.2 kg/14 wk; mean + 1.3 kg/14 wk). The amount of blood taken for laboratory studies was estimated. Although the estimated erythrocyte volume increased, the improvement was masked in most patients by enhanced growth. In two patients the target hemoglobin value of 10 gm/dl was reached, and in three patients transfusions were avoided. The reticulocyte count rose in dose-dependent fashion. In five patients protein malnutrition was not prevented, although intake of protein was as recommended. The gradual decrease in serum ferritin values indicated that mobilization of iron stores was adequate. Serum iron values decreased, although in general remaining within normal limits. In six patients the serum copper concentration was low and in two the serum aluminum concentration was slightly elevated. Two patients had several episodes of infection. We conclude that in rapidly growing infants and small children receiving peritoneal dialysis after nephrectomy, the maintenance or elevation of the hemoglobin concentration depends on several limiting and coinciding factors. We speculate that, when protein is limited, body growth has priority over erythropoiesis. A higher dose of erythropoietin might have evoked a better response in hemoglobin concentration but might also have resulted in progression of the protein deficit.