Clinical Endocrinology (1977) 7, Suppl., 59s-65s.
HYPERPARATHYROIDISM IN CHRONIC RENAL FAILURE S . E . P A P A P O U L O S , A . M . B R O W N J O H N , * B. J . R . J U N O R , * * F . P . M A R S H , * F . J . G O O D W I N , * W. H A T E L Y , * I . G . LEWIN, S . T O M L I N S O N , G.N . H E N D Y A N D J . L . H . O ’ R I O R D A N
Department of Medicine, The Middlesex Hospital, *Department of Nephrology, The London Hospital, London and **Medical Renal Unit, Royal Infirmav, Aberdeen SUMMARY
The high circulating concentrations of immunoassayable parathyroid hormone observed in.chronic renal failure are due to a number of factors. These include altered metabolism of the hormone and also end-organ unresponsiveness which may, indirectly, cause increased secretion of parathyroid hormone. The response of the overactive parathyroid glands to changes in plasma calcium and magnesium is variable and caution is needed in evaluating the suppressibility of parathyroid hormone secretion in acute studies. la-Hydroxylated derivatives of vitamin D can effectively suppress parathyroid gland overactivity. This effect may not necessarily be mediated through hypercalcaemia and vitamin D metabolites may act directly on the parathyroid glands. The genesis of hyperparathyroidism in chronic renal failure remains an enigma and treatment of the condition is difficult so that resort to surgical parathyroidectomy is still not uncommon. However, by the use of parathyroid hormone (PTH)immunoassays (Hendy & O’hordan, 1977) it has become easier to monitor the response of the parathyroid glands in acute and long-term studies, and thereby assist the clinical assessment of the response to different treatment regmens. A number of factors contribute to the elevated plasma concentrations of PTH observed in renal failure. Besides overactivity of the parathyroid glands in synthesis and release of PTH, altered metabolism of the hormone may be of importance. We have studied the metabolism of PTH in both normal and uraemic man (after infusion of exogenous PTH) using carefully characterized immunoassays specific for limited regions of the PTH molecule. In normal subjects, whereas the amino-terminal (biologically active) region of the molecule is rapidly cleared from the circulation (I,,, = 5 min), the inactive carboxy-terminal region persists for several hours (Papapoulos e f al., 1977). The mean metabolic clearance rate of amino-terminal PTH is lower in patients with chronic renal failure than in normal subjects, although as shown in Fig. 1 , there was some overlap between the values for the two groups.
Correspondence: Dr J . L. H . O’Riordan,Department of Medicine, The Middlesex Hospital, Mortimer Street, London W1N 8AA.
S.E. Papapoulos et al.
There is an inverse correlation between the degree of renal failure (as assessed by the plasma creatinine levels) and the metabolic clearance rate of amino-terminal PTH.Some anephric subjects can metabolize amino-terminal PTH as effectively as normal subjects, indicating that the kidney is not the only organ of importance in the metabolism of PTH.
Fig. I . Comparison of the metabolic clearance rate (MCR) of amino-terminal immunoreactive exogenous bovine PTH in normal subjects ( 0 ) and in patients with chronic renal failure; with intact kidneys (A) and without ludneys (a). The dotted lines represent the mean value for each group. (The immunoassay used was specific for the amino-terminal region of F'TH.)
Tissue unresponsiveness or end-organ resistance may, indirectly, be another contributary factor to hyperactivity of the parathyroid glands in renal failure. The resistance of the kidney can be demonstrated by a lack of change in plasma and urinary cyclic AMP after administration of exogenous PTH in patients with severe chronic renal failure (Todinson ef ul., 1976). The phosphaturic response in such patients has also been shown to be impaired (Evanson, 1966). The mechanism of the loss of response is not clear. As well as loss of functioning renal mass, the high plasma PTH may contribute to the resistant state at the receptor level, a is the case in patients with primary hyperparathyroidism with high circulating PTH (Todinson ef ul., 1976). The most important regulator of PTH secretion is the concentration of calcium. In the hyperparathyroidism of renal f d u r e , the parathyroid glands are generally sensitive to changes in plasma calcium. For example, as shown in Fig. 2 , infusion of calcium into a patient with chronic renal failure caused a rapid reduction in plasma VTH. It is of considerable interest to note that the suppression begins almost as soon as plasma calcium has started to rise and before hypercalcaemia has been produced. It is not clear yet whether it is the rise of calcium or the rate of the rise that is important. Although FTH concentrations decreasedvery rapidly, complete clearance of the hormone from the circulation was not observed during the infusion period, due presumably to the presence of long-lived fragments. Indeed apparent autonomy of the parathyroid glands during calcium infusion may be due merely to a failure to clear fragments from the circulation. Alternatively the residual plasma FTH may be due to a non-suppressible component of the secretion by the glands. In long-term studies the effect of altered metabolism of F"H is probably less important as a new steady state can be reached. Thus is was possible to study the long-term effects of
Hyperparathyroidism in CRF
Fig. 2 . The changes in circulating parathyroid hormone during infusion of calcium gluconate into a uraemic patient (R.D.). The immunoassay used was not region-specific: antiserum 199 (B/W 21 1/32) was used in an immunoradiometric (labelled antibody) assay system which was reactive with antigenic sites in both the amino- and carboxy-terminal regions of the PTH molecule. This assay was also used for the other studies reported here, with the exception of the studies of the MCR of exogenous bovine PTH in man (see Fig. 1).
changes of dialysate magnesium concentrations on parathyroid function in patients with chronic renal failure, as magnesium has been shown to be another regulator of parathyroid activity (Sherwood et al., 1970). A fall of plasma magnesium, produced by lowering dialysate magnesium. stimulated the parathyroid glands over a one and a half year period. This effect was clearly dependent on the initial degree of hyperparathyroidism. If there was already hyperparathyroidism, i t was unaffected by hypornagnesaernia. whereas when hyperparathyroidism was not severe initially, hypomagnesaemia produced ';1 significant rise in circulating PTH (Parsons & Papapoulos, unpublished results). The inter-relationships between PTH and vitamin D are of paramount importance. PTH, for example, stimulates the production of 1,25-dihydroxyvitamin D3 by the kidney and it is likely that vitamin D requires the presence of FTH to mobilize calcium from bone (Garabedian et ul., 1972; Fraser & Kodicek 1973; Garabedian er al., 1974). Administration of la-hydroxylated derivatives of vitamin D for the treatment of hyperparathyroidism of renal osteodystrophy, provides a different approach to the study of these interactions, as 1,25dihydroxyvitamin D3 production is impaired in uraemic patients (Mawer et ul., 1973 ; Haussler et ul., 1976). Altogether we have followed twenty-three patients with secondary hyperparathyroidism dialysed in three different centres and treated with la-hydroxyvitamin D3 for periods between 12 and 18 months. The biochemical response to la-hydroxyvitamin D3therapy in one group of ten patients is shown in Fig. 3 . They were treated for 16 months and over this period of time plasma calcium rose, as did plasma phosphate.
S.E. Papapoulos et al.
Calcium (rnmol/I 1
- Alkaline phosphatase ( I U
200 175 I50
125 100 75
Phosphate (rnmol/ I )
P T H (nglrnl)
2I C O
8 1 2 1 6
Fig. 3 . The biochemical response in plasma calcium. alkaline phosphatase, phosphate and PTH of a group of ten dialysed patients given la-hydroxyvitamin D, for 16 months. Means tSEM are shown.
Fie. 4. Radiograph of the wrbt of a patient with r e d ncksts treated with lahydroxyvitamin D, Before ( l ) , and after (2) treatment for 1 year.
Hyperparathyroidism in CRF
Fig. 5 . These four patients with hyperparathyroidism on haemodidysis were treated with la-hydroxyvitamin D, ( l a a H D , ) . Stippled areas represent normal ranges. Top left: W.R. was hyperdcaemic throughout and showed no response. Bottom left: K.D. remained normocalcaemic and also showed no response. Top right: S.W.responded to treatment with l a a H D , and never became hypercalcaemic; aluminium hydroxide was stopped and plasma phosphate rose and there was a transitory rise in PTH and alkaline phosphatase. Bottom right: G.H. showed a progressive fall of plasma PTH and alkaline phosphatase while plasma calcium remained unchanged.
The rise in plasma phosphate was not due to any changes of aluminium hydroxide treatment. It is also unlikely to be due to suppression of parathyroid overactivity in these dialysed patients. The increase of both plasma phosphate and calcium was most probably due to the effect of la-hydroxyvitamin D3on the intestinal absorption of these minerals. plapma alkaline phosphatase fell to normal in five of seven patients in whom it was initially raised; this fall was often preceded by a rise, or a 'flare', which did not indicate deterioration. The concentration of PTH fell progressively in all but one of these ten patients from
S.E. Papapoulos et al.
an initial value of 5.2920.7ng/ml (mean +SEMI to a value of 1.65?0.39ng/ml after 16 months of therapy. It was striking that the response often did not become apparent before the first 6 months of treatment in the majority of patients, and alkaline phosphatase and PTH concentrations continued to fall, if they had not already reached the normal range at the end of the 16 months. Radiological improvement, with healing of rickets and subperiostal erosions in some cases, was also observed (Fig. 4). The mean concentration of PTH in the group of the twenty-three patients as a whole, was 5.1 n g / d and fell to a mean of 1 . 8 n g / d during the study period. In nineteen patients a gradual reduction of plasma PTH was observed. The concentration of PTH became normal in thirteen of them. Four patients, however, showed no response to treatment and two of them (KD, WR) are illustrated in Fig. 5. Hypercalcaemia developed in seventeen of the twenty-three patients at some stage of the study period (from 2 weeks to 18 months after treatment). Because of the risk, therapy with la-hydroxyvitamin D3 has to be monitored carefully and the dose adjusted as required in each individual patient. Hypercalcaemia, however, is more likely to occur when therapy has been continued for a long time and there has been an improvement of the metabolic bone disease as evidenced by a fall in alkaline phosphatase and PTH concentrations. The suppression of parathyroid overactivity seemed generally to be associated with a rise of plasma calcium; hypercalcaemia per se was, however, not necessary for the reduction of PTH concentrations. A small rise in plasma calcium within the normal range could be associated with a significant fall of PTH. Thus the chronic response is analogous to the acute response to a calcium infusion. In one patient (GH) the concentration of PTH fell even though there was no significant change in her plasma calcium which remained in the normal range during the period of study (Fig. 5). It is possible therefore that a derivative of vitamin D may directly regulate the secretion of parathyroid hormone. It is clear that many factors can modify the response to la-hydroxylated compounds. For example, six of fourteen patients dialysed in the same centre were either resistant or only partially responded to la-hydroxyvitamin D3 therapy. Their pre-treatment plasma calcium (2.4620.05 mmol/l) was significantly higher (P < 0.01, Mann Whitney test) than the initial value for the other eight patients (2.2620.05) whose PTH concentrations fell into the normal range during the study period. In general, the lower the initial plasma calcium the lower the concentration of PTH at the end of the study. Plasma phosphate can also influence the response to treatment (Fig. 5 , patient SW), though it is usually difficult to know whether this is a direct effect of plasma phosphate changes on the parathyroid glands or whether it is due to concomitant changes of plasma calcium (Clarkson ef of., 1972). Treatment of the hyperparathyroidism of chronic renal failure has obviously benefitted from recent advances in our knowledge of the metabolism of vitamin D. It is clear however, that still further study is required to gain more insight into the aetiology and prevention of renal bone disease. ACKNOWLEDGMENTS
J.L.H. O’R is indebted to the Medical Research Council and the National L d n e y Research Fund for support. S.ES. is in receipt of the Astor Fellowship, The Middlesex Hospital Medical School. We are grateful to Professor B. Lythgoe, F.R.S. and Leo Laboratories Ltd, for supplying the la-hydroxyvitamin D3 used in these studes.
Hyperparathyroidism in CRF
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