D ietary phosphorus restriction (PR) prevents uremia in rats with nephrotoxic serum nephritis (NSN). One possible mechanism by which PR could be protective would be through the suppression of parathyroid hormone. To evaluate this possibility two separate protocols were designed. In the first rats were thyroparathyroidectomized (TPTX) before (n = 11) or 5 wk after (n = 7) NSN induction and compared to sham-operated parathyroid intact rats with NSN (n = 12). At the end of the 23-wk study, intact rats were azotemic, plasma creatinine 3.80±0.81 mg/100 ml vs. 0.65±0.07 for TPTX rats (P < 0.001). During the study 75% of intact rats died of uremia in contrast to none of the TPTX rats (P < 0.001). Renal histological damage was greatly diminished and calcification prevented in TPTX rats. The proteinuria of the heterologous phase was unaffected, but the protein excretion and hypertriglyceridemia (HTG) of the autologous phase were markedly decreased in the TPTX rats. The degree of HTG and proteinuria had a high positive correlation (P < 0.001). Late TPTX also produced significant decreases in proteinuria and HTG regardless of the degree of azotemia, and prevented azotemia if the plasma creatinine at the time of TPTX was ≤0.85 mg/100 ml.In additional studies selective parathyroidectomy (PTX) was performed. The adequacy of this procedure was documented by showing a similar fall in plasma Ca and urinary cyclic AMP in PTX animals as found in TPTX animals. However, selective PTX had no effect on proteinuria, histologic damage, or functional deterioration. These studies further showed that early, histologic damage and functional deterioration preceeded renal parenchymal calcification. Because animals were pair fed and both groups were given 1,25-dihydroxycholecalciferol to normalize serum Ca and P levels these studies exclude alterations in plasma Ca and P levels, dietary intake, urinary P excretion, and vitamin D administration in promoting the protective effect of TPTX on renal function.We conclude that TPTX is equally effective in preventing functional deterioration and more effective in reducing proteinuria in NSN than PR. The mechanism of this protective effect remains to be elucidated, since it does not primarily involve either the elimination of parathyroid hormone or the prevention of renal parenchymal calcification.