Calcium Metabolism in Early Chronic Renal Failure: Implications for the Pathogenesis of Hyperparathyroidism

Studies in the past showed elevated immunoreactive parathyroid hormone (PTH) serum values in early renal failure, but the assays used in these studies could not discriminate between bioinactive fragments of the PTH peptide and biologically active hormone. The availability of a sensitive PTH assay, which quantitates intact hormone, now allows the analysis of biologically active PTH in renal failure. To characterise more precisely the point of onset of hyperparathyroidism in the course of chronic renal failure and its relation to 1,25-dihydroxyvitamin D3 1,25(OH)2D3, we measured plasma intact PTH and vitamin D metabolite serum values in 63 non-nephrotic uraemic patients (male n=35, female n=28, age 31–78 years) with incipient (GFR 60–90 ml/min per 1.73 m3, n=19) mild (GFR 40–60, n=22) and moderate (GFR 20–40, n=22) renal failure, and in 22 age-matched healthy control subjects. Intact PTH concentrations were negatively correlated with GFR (r=−0.57, P<0.001). Median plasma intact PTH values (normal range 1.2–6 pmol/1) were 5.6 (range 2.2–13.0) in incipient, 8.1 (2.9–24.0) in mild, and 13.0 (5.4–59.0) in moderate renal failure. Intact PTH values in incipient renal failure were significantly greater than in 22 age-matched control subjects (P<0.01). The decline of GFR was paralleled by a progressive decrease in 1,25(OH)2D3 serum values (r=0.44, P=0.001). Median values of the hormone (normal range 35–90 pg/ml) were 32 (range 20–66) in incipient (P<0.01 vs age-matched control subjects), 34 (22–74) in mild, and 26 (17–39) in moderate renal failure. In all three groups, mean serum phosphate and total calcium concentrations (corrected for serum protein) were within the normal range. Serum 25-hydroxyvitamin D 25(OH)D was positively correlated with serum 1,25(OH)2D (r=0.51, P<0.001) in the patients with early renal failure. We conclude: (1) Hyperparathyroidism in incipient renal failure occurs at normal serum phosphate and calcium values. (2) Hyperparathyroidism, as measured by intact PTH values, is already present in a sizable proportion of patients with a GFR of 90–60 ml/min. (3) Decreased 1,25(OH)2D values in very early RF, despite elevated intact PTH, points to abnormal regulation of biosynthesis of 1,25(OH)2D3. (4) Abnormal regulation of vitamin D metabolism, i.e. substrate dependency of 1,25(OH)2D3 production, occurs early in chronic renal failure. Since 1,25(OH)2D3 suppresses parathyroid function, our data suggest that relative or absolute 1,25(OH)2D3 deficiency is involved in the pathogenesis of secondary hyperparathyroidism in incipient renal failure.