Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish type--implication of EPO, transferrin and transcobalamin losses.

Congenital nephrotic syndrome of the Finnish type (CNF) is due to NPHS1 mutation and is responsible for a variety of urinary protein losses. We report the case of a 4-month-old girl with a particularly severe form (proteinuria approximately 150 g/l) of CNF. She developed severe non-regenerative anaemia requiring bi-monthly blood transfusions despite daily EPO (600 UI/kg) and iron supplementation. Epoetin pharmacokinetics revealed a urinary loss of 27% of the given dose within the first 24 h after IV injection. However, plasma levels remained increased after 24 h (228 UI/l). Plasma transferrin and transcobalamin levels were undetectable. Atransferrinaemia and atranscobalaminaemia seem to be responsible for disturbed erythropoiesis.

Persistently elevated serum transcobalamin II in a patient with cerebral malaria and typhus infections.

A 25-year-old man presented with a history of fever, chills and vomiting for three days. The parasite count was 207 ring-forms of P. falciparum per 1000 red cells. He developed hemoglobinuria and excreted hemoglobin in the urine 0.20-0.30 g/dl for 14 days during admission. Many blood transfusions were administered for correcting anemia. Although the malarial parasites disappeared one week after anti-malarial therapy, however, the fever and hemoglobinuria persisted. The Weil-Felix reaction OXK was positive with a titre of 1:40 on admission and increased to 1:160 on the second week. Chloramphenical and prednisolone were given for treatment of typhus fever and all symptoms subsided. Serum TCII levels were found to be increased and persisted high during the hemoglobinuria. The clearance of TCII was lower and increased relatively slowly to the normal level on day 30. On the other hand, TCII excretion in the urine was found to be increased during hemoglobinuria. These findings indicate that the catabolism and clearance of TCII in this patients is impaired with increased TCII excretion in the urine in parallel to the hemoglobinuria. Serum TCII level is, therefore, increased and persistently high in a patient with malaria and typhus fever infections with hemoglobinuria.

Increased circulating levels of transcobalamin II in malarial patients with renal involvement.

Vitamin B12 and its binding proteins were measured in the serum and urine of four patients with Plasmodium falciparum who had renal insufficiency. The results showed that these patients had elevated serum transcobalamin II (TCII) levels which decreased to the normal level after recovery from azotaemia. There were direct relationships between serum TCII levels and blood urea-nitrogen or creatinine concentrations. The clearance and urinary excretion of vitamin B12 and TCII were significantly lower in the patients' group than in normal subjects. All these findings indicated that elevated serum TCII could occur in P. falciparum patients with renal insufficiency. This is probably caused by a reduction in renal plasma flow and glomerular filtration rate (GFR), secondary to a low or ineffective blood volume. The reduced GFR, in turn, reduces the TCII-B12 that filters through the glomeruli, resulting in decreased TCII-B12 uptake by the renal tubules, and thus slows down the TCII degradation by lysosomal enzymes. The decreased TCII catabolism therefore prolongs the TCII survival in the circulation and probably stimulates TCII synthesis and secretion in a feedback mechanism.

Transcobalamin II receptor interacts with megalin in the renal apical brush border membrane.

Purified human transcobalamin II receptor (TC II-R) binds to megalin, a 600 kDa endocytic receptor with an association constant, K(a), of 66 n M and bound(max) of 1.1 mole of TC II-R/mole of megalin both in the presence and absence of its ligand, transcobalamin II (TC II). Immunoprecipitation followed by immunoblotting of Triton X-100 extracts of the apical brush border membrane (BBM) from rabbit renal cortex revealed association of these two proteins. (35)[S]-TC II complexed with cobalamin (Cbl; Vitamin B(12)) bound to Sepharose-megalin affinity matrix and the binding was enhanced 5-fold when TC II-R was prebound to megalin. Megalin antiserum inhibited both the TC II-R-dependent and -independent binding of (35)[S]-TC II-Cbl to megalin, while TC II-R antiserum inhibited only the TC II-R-dependent binding. In rabbits with circulating antiserum to megalin, renal apical BBM megalin was present as an immune complex, but its levels were not altered. However, the protein levels of both TC II-R and the cation-independent mannose 6-phosphate receptor (CIMPR) were drastically reduced and the urinary excretion of TC II, albumin, and other low-molecular weight proteins was significantly increased. These results suggest that megalin contains a distinct single high-affinity binding site for TC II-R and their association in the native renal BBM is important for tubular reabsorption of many proteins, including TC II.