T he main objective of this study was to determine whether the principal abnormality of thyroid function observed in patients with chronic renal failure, low serum triiodothyronine (T₃) concentration, causes hypothyroidism at the tissue level. A partially nephrectomized (Nx) uremic rat model was developed and the following parameters of thyroid function were assessed: serum total thyroxine (TT₄), total T₃ (TT₃), and thyrotropin and liver T₃ content, and activity of two thyroid hormone-dependent enzymes, mitochondrial α-glycerophosphate dehydrogenase (α-GPD) and cytosol malate dehydrogenase (MDH). The results were compared to those of intact control (C), thyroidectomized (Tx), and nephrectomized-thyroidectomized (NxTx) littermates.Results expressed as mean±SEM showed that Nx rats had a fivefold increase in blood urea nitrogen, (112±20 mg/dl in Nx, and 22±1 mg/dl in C) and manifested all the changes of of thyroid function observed in uremic men, including a low serum TT₃ level (30±7 ng/dl in Nx and 50±6 ng/dl in C). In the liver, T₃ was significantly reduced (18±2 ng/total liver in Nx and 35±3 ng/total liver in C) as well as the activities of αGPD (8.8±1.0 and 16.1±1.5 ΔOD/min per total liver in Nx and C, respectively) and MDH (6.3±1.6 and 12.6±2.2 U/total liver in Nx and C, respectively). The reduction in liver enzyme activities correlated significantly with the decrease in T₃ content.The changes in Tx rats were as expected, showing a profound reduction in serum hormone levels, liver T₃ content, and liver enzyme activities. Serum thyrotropin was markedly elevated to 2,390±212 ng/ml as compared to 703±61 in C and 441±87 ng/ml in Nx rats. The NxTx rats showed the combined effects of nephrectomy and thyroidectomy; blood urea nitrogen was elevated to 203, and serum levels of TT₄, TT₃, and thyrotropin were 0.4, <10, and 2,525, respectively. Total liver T₃ and αGPD and MDH were strikingly low; the corresponding values were 3.5, 2.4, and 2.5.l-triiodothyronine replacement (0.4 μg/100 g body wt/d) for 4 wk in the Nx rats resulted in significant increases in liver enzyme activities, αGPD and MDH rose by 70 and 60% over their respective basal values without alteration in the severity of azotemia.From these data, we conclude that the reduction of liver T₃ content in the uremic rats, accompanied by a decrease in αGPD and MDH activity, indicates the presence of hypothyroidism at the tissue level. Restoration of enzyme activities toward normal levels after T₃ administration provided further supporting evidence that the diminution in liver enzyme activity was causally related to tissue T₃ deficiency.