Factors in the development of secondary hyperparathyroidism during graded renal failure in the rat

Abstract

Secondary hyperparathyroidism (2° HPT) develops as a result of renal failure. Hypocalcemia, phosphorus retention, calcitriol deficiency and skeletal resistance to the calcemic action of parathyroid hormone (PTH) are closely interrelated pathogenic factors important for the development of 2° HPT in renal failure. Since previous studies have mainly focused on advanced renal failure, only limited data are available in early renal failure. The goal of the present study was to evaluate how alterations in the dietary calcium and phosphorus composition affect the factors known to contribute to the genesis of 2° HPT in early and more advanced renal failure. To achieve this goal, graded differences in renal function were surgically induced in 453 rats while the dietary content of calcium and phosphorus was varied. Three different diets were used: (1) a high phosphorus diet (HPD), to induce phosphorus retention and stimulate 2° HPT; (2) a high calcium diet (HCaD), to inhibit calcitriol synthesis; and (3) a moderate calcium-moderate phosphorus diet (MCaPD), to separate the effects of high dietary phosphorus and calcium. Based on the serum creatinine (S(Cr)) concentration rats were assigned to one of four different groups: (1) normal renal function (S(Cr) ≤ 0.3 mg/dl); (2) mild renal failure (S(Cr) 0.4 to 0.6 mg/dl); (3) moderate renal failure (S(Cr) 0.7 to 0.8 mg/dl); or (4) advanced renal failure (S(Cr) ≥ 0.9 mg/dl). As the severity of renal failure increased, progressive 2° HPT developed in each of the dietary groups. In the HPD group, the increase in PTH in normals from 47 ± 2 to 135 ± 14 pg/ml in mild renal failure (P < 0.001) was associated with hyperphosphatemia, a decrease in calcitriol and a decreased calcemic response to PTH. In the HCaD group, the increase in PTH in normals from 42 ± 2 to 74 ± 4 pg/ml in mild renal failure (P < 0.001) was associated with a decrease in calcitriol. In the MCaPD group, 2° HPT developed (40 ± 2 vs. 70 ± 4 pg/ml, normals vs. mild renal failure, P < 0.001) despite normal serum calcium, phosphorus and calcitriol levels; however, a decreased calcemic response to PTH was observed. In advanced renal failure, progressive increases of PTH were observed in all groups, but PTH levels were approximately three-fold greater in the HPD than the HCaD and MCaPD groups (410 ± 24, 114 ± 14 and 138 ± 17 pg/ml, respectively; P < 0.001). While serum calcitriol levels were markedly decreased in the HPD and HCaD groups in advanced renal failure, normal calcitriol levels were present in the MCaPD group. In summary, the development and magnitude of 2° HPT in the HPD group could be best explained by the contribution of several additive factors which included; hypocalcemia, phosphorus retention, a calcitriol deficiency and a decreased calcemic response to PTH. In the HCaD group, a calcitriol deficiency appeared to be the most important factor for the development of 2° HPT. In the MCaPD group, a decreased calcemic response to PTH, which may have been due to uremia, was the only factor to which 2° HPT could be attributed.