Both transferrin and the iron it carries are lost in the urine in the nephrotic syndrome. Patients may develop hypochromic microcytic anemia and synthesis of transferrin, a protein regulated in large part by iron availability, is increased. Transferrin synthesis has also been reported to be increased in liver slices from rats with hereditary analbuminemia, and their plasma transferrin levels are increased, suggesting that transferrin synthesis may be stimulated by processes other than iron depletion in this hypoalbuminemic condition. Transferrin metabolism was studied in rats with Heymann nephritis (HN), in a strain of Sprague-Dawley (SD) rats with hereditary analbuminemia [Nagase analbuminemic rats (NAR)], and in normal SD rats. Plasma transferrin concentration and mass was decreased significantly in HN, but increased in NAR. Transferrin synthesis was increased both in NAR (measured either as the disappearance of [125I] labeled transferrin or as the incorporation of [3H] phenylalanine) and in HN (incorporation of [3H] phenylalanine). The fractional rate of transferrin catabolism was unchanged in NAR. Thus transferrin mass was increased in NAR entirely as a consequence of increased synthesis. Transferrin and albumin synthesis correlated with one another in both HN and SD (P < 0.001). Transferrin mRNA was increased in both HN and NAR and was unaffected by administration of iron to HN. Hepatic transferrin and albumin mRNA levels were also correlated positively in HN and SD, suggesting that increased hepatic synthesis of both proteins might be responding to the same stimuli. Transferrin gene transcription was increased in both HN and NAR and was unaffected by administration of iron to HN. Transferrin mRNA was not increased in the testis in either HN or NAR, suggesting that augmentation in transferrin gene expression is driven by a non-iron dependent process and is confined to the liver.