Intact parathyroid hormone levels in renal insufficiency - Springer Link

Calcif Tissue Int (1995) 57:32%335

Calcified Tissue

h~emational

9 1995 Springer-Verlag New York Inc.

Intact Parathyroid Hormone Levels in Renal Insufficiency V. T. Fajtova, 1 M . H. S a y e g h , z N. H i c k e y , 2 P. A l i a b a d i , 3 J. M . L a z a r u s , z M . S. L e B o f f 1

1Department of Medicine, Endocrinology Hypertension Division, Brigham and Women's Hospital, Boston, Massachusetts 02115 2Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115 3Department of Radiology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115 Received: 2 February 1995 / Accepted: 26 April 1995 Abstract. To define the onset of the rise in intact parathyroid

hormone (PTH) levels in renal insufficiency, we conducted a cross-sectional study of parameters of mineral metabolism in patients with varying degrees of renal impairment. Using an immunoradiometric assay to measure intact PTH levels, we found elevations in intact PTH levels as creatinine clearance approaches 60 ml/minute (serum creatinine near 1.8) and a significant inverse relationship between indices of renal function and intact PTH levels (r = -0.60, P < 0.001 for intact PTH and creatinine clearance). Calcium and phosphate levels correlate less strongly with the degree of hyperparathyroidism (r = "0.39, P < 0.001 for total calcium; r = 0.31, P < 0.05 for phosphate). As a group, only patients with severe renal failure (creatinine clearance

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Fig, 3. Comparison of total serum calcium (a), phosphate (b), 1,25vitD (c) and alkaline phosphatase (d) concentrations. Groups with mild. moderate, and severe renal insufficiency are as described for Figure 2. All of these parameters changed significantly, as renal function worsened. Total serum calcium concentration was significantly lower in the group with severe renal faiture than those in mild

tion and the resulting hyperparathyroidism. Early phosphate retention may lead to inadequate activation and action of vitamin D, which may contribute to end organ resistance to PTH action and hypocalcemia. In addition, reduced sensitivity of the parathyroid glands to the suppressive effects of

MILD MODERATE SEVERE renal insufficiency (P < 0.0l). The serum phosphate concentration and alkaline phosphatase activity were significantly elevated in the group with s e v e r e renal failure whereas the 1,25vitD levels were lower compared with the other two groups with less severe renal dysfunction (P < 0.01).

calcium may lead to chronic stimulation and increase in parathyroid cell mass. Chronically, this leads to parathyroid overstimulation, hyperplasia, and hypersecretion. We demonstrated a significant correlation between creatinine clearance and serum calcium levels as well as creat-

V. T. Fajtova et al.: Intact PTH in Renal Insufficiency

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Fig. 4. Correlation of intPTH with nPTH. IntPTH and nPTH are highly correlated regardless of the degree of renal insufficiency (r = 0.90), even in the high range. This analysis includes samples from all patients who were screened for this study (n = 37). Some of these patients were excluded from the rest of the study because they were taking medications that may interfere with mineral metabolism.

inine clearance and phosphate levels, however, these levels were only significantly abnormal in the group of patients with s e v e r e renal insufficiency (creatinine clearance less than 20 ml/minute). At this degree of renal failure, parathyroid hyperfunction is well established. Similarly, whereas there is a significant correlation between 1,25vitD levels and creatinine clearance when the whole study population is analyzed (P < 0.05), 1,25vitD levels are low only in the group of patients with s e v e r e renal insufficiency (Tables 1, 3). Functional hyperparathyroidism may compensate in m i l d and m o d e r a t e renal insufficiency, and drive lc~-hydroxylation of vitamin D, without notable changes in serum total and ionized calcium. Multivariate analysis of several parameters of mineral metabolism identifies creatinine clearance as the strongest independent predictor of elevated intPTH levels, with serum calcium playing a lesser role, and phosphate and 1,25vitD having little independent contribution (Table 2). However, in more advanced renal insufficiency, calcium, phosphate, and 1,25vitD levels are all abnormal, and thus may contribute independently to the elevations in intPTH levels. Therefore, other than in declining renal function itself, we have not been able to identify any static metabolic parameters that may initiate the rise in serum intPTH levels in patients with mild renal insufficiency. Alkaline phosphatase activity, as a marker of bone turnover, correlates well with the degree of h y p e r p a r a t h y roidism, being most elevated in the group of patients with s e v e r e renal insufficiency. Uremic patients demonstrate skeletal resistance to the action of PTH [28], however, the elevations of alkaline phosphatase in our subjects suggest that there may be increased resorption of calcium from bone

in this group of nondialized patients. By multivariate analysis, intPTH rather than creatinine clearance appears to be a major independent determinant of alkaline phosphatase activity (Table 2), suggesting that the skeletal effects of renal failure are largely PTH mediated. Bone resistance to PTH action in uremic patients may serve to protect the bone by attenuating bone resorption, but may also exacerbate the hyperparathyroidism by diminishing the calcemic response to elevations in PTH levels. Uremic and hyperplastic parathyroid gland tissue may secrete increased proportion of PTH fragments [29], thus elevating the nPTH out of proportion to the intPTH. In addition, the clearance of intPTH may be influenced by the renal dysfunction to a lesser degree than nPTH [2]. However, we found an excellent correlation between the intPTH levels and PTH as measured by a radioimmunoassay specific for the N-terminal portion of the PTH molecule, suggesting that the N-terminal measurement is valid in the whole spectrum of renal failure. IntPTH appears to accurately assess biologically significant PTH levels, and not to be effected by circulating PTH fragments. Thus, studies utilizing the older, N-terminal assay for determination of PTH levels do reflect the true status of the calcium homeostatic system in patients with renal failure. Our data may underestimate the severity of renal impairment in this patient population, since the creatinine clearance overestimates the glomerular filtration rate when compared with glomerular filtration rate measured by inulin clearance [30]. This holds true for all degrees of renal impairment. Therefore, static measurements demonstrate abnormal calcium, phosphate, and 1,25vitD levels even later in renal insufficiency than is estimated here (as well as in most of the studies performed to investigate this question). In this study, the creatinine clearance was not corrected for body habitus. Such a correction may redistribute the data, but should not alter the overall findings. We included serum creatinine levels in our analysis, to allow comparison with easily accessible clinical measurements. We found intact PTH levels to be elevated in nonnephrotic patients with mild to moderate renal failure, before abnormalities in serum calcium, phosphate, or vitamin D become apparent. Since intPTH is less dependent on renal function for its clearance than both active and inactive PTH fragments, these observations represent parathyroid hypersecretion in patients with mild to moderate renal insufficiency. Dynamic studies that perturb calcium, phosphate, 1,25vitD, and PTH levels in a way that mimic the everyday life of our patients, would be necessary to definitively elucidate the pathogenesis of hyperparathyroidism in early renal failure. These studies emphasize the necessity to address the development of secondary hyperparathyroidism early in the course of renal insufficiency, both clinically and experimentally.

Acknowledgments. CLINFO at Brigham and Women's Hospital,

Boston, MA, is supported by the GCRC Grant 5-MO1-PR02635. We would like to express our appreciation to Mr. Ray Gleason for his assistance with the statistical analysis of our data.

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