Relationship between magnesium and secondary hyperparathyroidism during long-term hemodialysis

Relationship Between Magnesium and Secondary Hyperparathyroidism During Long-term Hemodialysis Peter Pletka, Daniel S. Bernstein, Constantine L. Hampers, John P. Merrill, and Louis M. Sherwood Twenty-six patients w i t h chronic renal failure treated by long-term hemodialysis were studied. Radiologic parathyroid bone disease was observed in 15 patients, and in these, serum parathyroid hormone (PTH) levels were significantly higher (p < 0.01) than in those w i t h no bone disease. In 14 patients, dialysate magnesium concentration was raised from the routine of 1.5-2.5 meq/liter (high) for a period of 2 mo, and in 12 patients it was reduced to 0.5 m e q / l i t e r (low). A double crossover was then performed for a further 2 mo. The increase in dialysate magnesium resulted in a decrease in serum PTH, calcium, and phosphate concentration, w h i l e a decreased dialysate magnesium caused a marked rise in serum PTH without a concomitant increase in serum cal-

cium and phosphate. Following the crossover, the reciprocal relation between serum PTH and dialysate magnesium was again evident. The changes in serum PTH levels w i t h different dialysate magnesium concentrations suggest that magnesium and calcium influence parathyroid gland secretion in a similar manner, high levels suppressing PTH secretion and low levels stimulating it. The decrease in serum calcium and phosphate w i t h low circulating PTH in high magnesium dialysis is probably due to decreased bone resorption, w h i l e the relative lack of change in serum calcium and phosphate concentrations w i t h high PTH levels in low-magnesium dialysis is consistent w i t h end organ refractoriness.

E N A L O S T E O D Y S T R O P H Y is a c o m m o n complication in patients with chronic renal failure maintained by means of chronic hemodialysis and is associated with increased levels of circulating serum parathyroid hormone (PTH). 1-7 Although serum PTH has been shown to increase with the duration of dialysis, 2 it may be suppressed temporarily by intravenous infusions of calcium and by the use of high calcium dialysis. 5'6 It has been suggested, therefore, that long-term high-calcium dialysis may be beneficial in reducing the incidence of secondary hyperparathyroidism, while low-calcium dialysis may aggravate PTH-induced bone disease. 5 Although concentrations of serum calcium correlate poorly with circulating P T H in individual patients with chronic renal failure, the concentrations of calcium and phosphate and their product generally increase with more severe secondary hyperparathyroidism.

R

From the Departments o f Medicine, Peter Bent Brigham Hospital and Beth Israel Hospital, and the Department o f Nutrition, Harvard School o f Public Health, Boston, Mass. Part o f this study was presented at the 53rd meeting of the Endocrine Society, 1971, San Francisco, Calif. Received for publication November 13, 1973. Supported by USPHS Grant HD08825, a grant from the John A. Hartford Foundation, Inc., and the Fund for Research and Teaching, Department o f Nutrition, Harvard School o f Public Health. Reprint requests should be addressed to Peter Pletka, M.D., The Memorial Hospital, 119 Belmont Street, Worcester, Mass. 01605. 9 1974 by Grune & Stratton, Inc.

Metabolism,Vol. 23, No. 7 (July), 1974

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E x p e r i m e n t s in v i v o a n d in v i t r o h a v e s h o w n t h a t m a g n e s i u m affects p a r a t h y r o i d g l a n d f u n c t i o n in a m a n n e r s i m i l a r t o t h a t o f c a l c i u m , 8-t~ w i t h h i g h levels s u p p r e s s i n g P T H s e c r e t i o n a n d l o w l e v e l s s t i m u l a t i n g it. P r e l i m i n a r y o b s e r v a t i o n s f r o m t h i s l a b o r a t o r y h a v e i n d i c a t e d , f u r t h e r m o r e , t h a t a l t e r a t i o n s in d i a l y s a t e m a g n e s i u m c o n c e n t r a t i o n s are a s s o c i a t e d w i t h r e c i p r o c a l c h a n g e s in t h e levels o f c i r c u l a t i n g h o r m o n e . " In p a t i e n t s o n c h r o n i c h e m o d i a l y s i s , t h e effects o f P T H o n b o n e a n d t h e k i d n e y m a y be i n f l u e n c e d b y t h e e x t r a c e l l u l a r c o n c e n t r a t i o n o f m a g n e s i u m . R e d u c t i o n in s e r u m m a g n e s i u m h a s b e e n rep o r t e d to b l u n t t h e effect o f P T H o n b o n e in t h e p r e s e n c e o f i n c r e a s e d l e v e l s o f t h e h o r m o n e . ~2"~3 It w o u l d a l s o a p p e a r t h a t e x t r e m e l y l o w l e v e l s o f m a g n e s i u m m a y a c t u a l l y d e c r e a s e s e c r e t o r y a c t i v i t y by a n o t h e r w i s e s t i m u l a t e d gland.~4-~7 T h e a d m i n i s t r a t i o n o f m a g n e s i u m m a y r e s t o r e p a r a t h y r o i d h o r m o n e a c t i o n a n d / o r secretion.IS,18 T h i s s t u d y is a n a t t e m p t to d e f i n e t h e effects o f v a r y i n g d i a l y s a t e m a g n e s i u m c o n c e n t r a t i o n s o n c i r c u l a t i n g levels o f P T H a n d o t h e r a s p e c t s o f s e c o n d a r y I h y p e r p a r a t h y r o i d i s m in p a t i e n t s m a i n t a i n e d by m e a n s o f c h r o n i c h e m o d i a l y s i s . MATERIALS AND METHODS Twenty-six patients with chronic renal failure who were maintained on chronic hemodialysis were randomly selected from the renal service of the Peter Bent Brigham Hospital and divided into two groups depending on the days on which they were dialyzed. In group I (14 patients), dialysate magnesium concentration was increased from a "routine" 1.5 to 2.5 meq/liter (high) for a period of 2 mo. In a crossover study; dialysate magnesium was theft reduced from 2,5 to 0.5 meq/liter (low) for a subsequent 2-mo period. In group II (12 patients), magnesium dialysate was decreased from 1.5 to 0.5 meq/liter for 2 mo and then increased to 2.5 meq/liter for an additional 2 mo: All patients had been dialyzed previously three times a week with a twin coil artificial kidney aga!nst a dialysis bath containing 1.5 meq/liter of magnesium and 2.6 meq/liter of calcium. Dialysate calcium concentration was unchanged during the study. All patients studied had been on dialysis for periods of 2 12 mo, and most were waiting for renal homotransplantation. They regularly received folic acid, a multivitamin preparation not containing vitamin D, and aluminum hydroxide gel 60-90 ml/day. Although the dose of aluminum hydroxide varied from patient to patien L the amounts taken by each individual patient throughout the study were maintained as constant as possible in order to minimize alterations in intestinal phosphate absorption, No patient received vitamin D or calcium supplements. Arterialized blood tYom the shunt or the AV fistula was obtained at the time of connection to the dialysis machine for the estimation of serum PTH, calcium, phosphate (inorganic phosphate), magnesium, and alkaline phosphatase. These measurements were obtained on two occasions immediately prior to the commencement of the study and served as controls. They were again measured after 1, 2, 4, and 8 wk of the protocol. After the crossover from high- to low- or low- to high-magnesium dialysis, blood was again collected at similar intervals. The last values obtained before the crossover in both groups acted as controls for the subsequent period. Serum creatinine, blood urea nitrogen, alkaline phosphatase, and albumin were measured at monthly intervals. Serum PTH was measured by radioimmunoassay as described previously. 4 Samples were run in duplicate at two different concentrations and were related to equivalent concentrations of highly purified bovine PTH (kindly supplied by Dr. G. D. Aurbach). Normal values obtained by this radioimmunoassay ranged from undetectable to 0.2 ng/ml of bovine PTH equivalent. The lower limit of detection was 0.1 ng/ml. All patients in this study had detectable values, and these were elevated in 23 of the 26 patients. Serum calcium, phosphate, alkaline phosphatase, and albumin were measured routinely in the laboratory of the Peter Bent Brigham Hospital. Serum magnesium was measured by the method of Orange and Rheim 19

621

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Radiologic bone surveys were made that included examination of the skull, chest, spine, pelvis, and hands within 1 mo of the commencement of the study. Radiologic changes were graded as follows: mild, early cortical bone reabsorption, particularly in the phalanges; moderate, "lacey" trabeculated pattern in the hands and early resorption in the sacroiliac and acromioclavicular joints; severe, fraying of all subperiostial margins of the phalanges and changes in the sacroiliac and acromioclavicular joints. Statistical calculations were performed using an analysis o f variance for each parameter in either the high- or low-magnesium dialysis group to evaluate significant changes with time. When the F scores obtained showed a p value of less than 0.05, paired tests between control and subsequent determinations were performed. Comparisons of data between two individual groups were made using Student's t test for independent mean. RESULTS

The clinical data for the 26 patients in the study are shown in Table 1. The ages of the patients, the degree of azotemia, and the duration of hemodialysis are similar in both groups. All patients had been on dialysis for periods ranging from 2 to 12 mo, and the mean duration of dialysis was 7.7 mo in G r o u p I and 7.5 mo in group II. By chance, the incidence of parathyroid bone disease was higher in group I, affecting 11 of the 14 patients, while only four of the 12 patients in group II showed radiologic evidence of bone involvement. Nevertheless, all patients had detectable levels of P T H in the serum. The level of P T H in the serum was greater than normal in all 14 patients in group I and in nine of the 12 patients in group II. The higher incidence of parathyroid bone disease in group I was associated with higher mean serum concentrations of PTH (p < 0.01) and mean serum phosphate levels (p < 0.05) than in group II. However, serum calcium, alkaline phosphatase, and magnesium were not significantly different in the groups. The discrepancy between these findings in the two groups was surprising, since the method of selection was strictly based on the days o f dialysis, i.e., Monday, Wednesday, and Friday (group I), and Tuesday, Thursday, and Saturday (group II), and no other known criteria were used. When patients in both groups were subdivided on the basis of either the presence or absence of radiologic bone disease (Fig. 1), only the mean serum P T H differed significantly (p < 0.01). Mean serum phosphate differed slightly but not significantly (p < 0.1), while serum calcium, alkaline phosphatase, and magnesium were similar in both groups. []With Rodioiogic BoneDiseose, n:t5

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The relationship between serum P T H and serum magnesium in group I is shown in Fig. 2. All values are expressed as a mean ~_ SE. During high-magnesium dialysis, serum magnesium increased from 3.23 4- 0.11 to 3.85 4- 0.18 meq/liter after 1 wk, but subsequently decreased to 3.00 4- 0.09 meq/liter after 8 wk despite continuation of high-magnesium dialysis. Serum P T H decreased over the first 4 wk from 2.6 4- 0.3 to 1.7 J= 0.3 ng/ml (p < 0.05) and then remained unchanged for the remainder of the high-magnesium dialysis period. The associated changes in serum calcium and phosphate are shown in Table 2. Serum calcium decreased from 9.39 • 0.17 to 8.98 4- 0.21 rag/100 ml after 2 wk and serum phosphate from 7.85 4- 0.27 to 7.08 4- 0.37 mg/100 ml. The major decline in calcium and phosphate coincided with the major decrease in serum PTH. Serum phosphate subsequently continued to decrease slightly to 6.73 40.29 rag/100 ml after 8 wk, but serum calcium remained unchanged. Following the crossover from high to low magnesium, serum magnesium decreased markedly within 1 wk from 3.00 4- 0.09 to 1.94 4- 0.08 meq/liter, and this was associated with a reciprocal and significant rise in serum PTH from 1.7 4- 0.3 to 5.1 =a 1.0 ng/ml. However, mean serum calcium and phosphate remained unchanged during this period of maximal increase in PTH, and although both increased subsequently, the rise was not significant. When the patients in group II were initiated on low-magnesium dialysis followed by high-magnesium dialysis, the reciprocal relationship between serum magnesium and serum P T H was again evident (Fig. 3). Serum magnesium decreased from 3.15 4- 0.14 to 1.89 4- 0.07 meq/liter, while serum PTH increased from 0.8 4- 0.17 to 1.6 4- 0.4 ng/ml. The maximum increase in serum P T H occurred during the first week of low magnesium dialysis. Serum calcium and phosphate remained unchanged during this period of maximal hormonal increase. Following the crossover from low to high magnesium, serum magne-

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sium increased to 3.05 • 0.05 meq/liter, while serum PTH decreased to 0.6 • 0.1 ng/ml during the same period. The decrease in serum P T H was gradual throughout this time, but serum calcium fell abruptly during the first week from 9.65 • 0.29 to 8.37 • 0.17 mg/100 ml, and although it rose to 8.87 • 0.20 rag/100 ml after 8 wk, this value was still lower than that attained before crossover. Serum phosphate decreased from 7.04 • 0.55 before the crossover to 6.29 • 0.49 mg/100 ml, but this decrease was not significant. Serum creatinine, albumin, and alkaline phosphatase were unchanged with both low- and highmagnesium dialysis. Pruritis was a c o m m o n symptom among some patients throughout the course of the study. Nine of the 14 patients in group I and five of the 12 patients in group II had pruritus while undergoing regular hemodialysis (Table 1). Highmagnesium dialysis was associated with improvement of this symptom in six of the nine patients in group I and, when followed by low-magnesium dialysis, resulted in worsening of the symptoms or development of pruritus in ten patients. Similarly, in group I1 low-magnesium dialysis resulted in worsening of pruritus in all five patients, with improvement in three of the five when they were switched from low- to high-magnesium dialysis. DISCUSSION

Secondary hyperparathyroidism may be progressive during long-term hemodialysis I 6 and is characterized by increasing levels of serum PTH. 4 Serum calcium and alkaline phosphatase, despite a tendency to be higher in patients with more severe parathyroid disease, are not reliable diagnostic criteria. In the current study, the serum P T H and phosphate, although variable, correlated better than did calcium and alkaline phosphatase with the incidence of radiologic bone disease. There is currently considerable disagreement among investigators concerning

MAGNESIUM, HYPERPARATHYROIDISM, AND HEMODIALYSIS

627

the peptide (or peptides) being measured in peripheral blood as PTH. Berson and Yalow 2~ originally suggested that different immunochemical fragments of PTH were present in human plasma. More recent studies z~43 have confirmed this concept, although disagreement exists as to the biologic activity of these fragments.Z3 25 The values determined in the present study felt on the same standard curve for purified bovine PTH, 4'26 and the hormone being measured increased and decreased appropriately during acute change in serum calcium. 6 Furthermore, serial measurements of PTH were made in the patients studied, and they correlated well with other laboratory indices of parathyroid function. In patients being maintained by hemodialysis, a factor that may be important in regulating serum calcium is the level of dialysate calcium. Fournier et al. reported that high-calcium dialysis (dialysate calcium of 6 mg/100 ml or higher) 5 resulted in lower serum PTH levels than low-calcium dialysis (dialysate calcium of less than 5.6 mg/100 ml). A net transfer of calcium from either dialysis bath to the patient or from the patient to the dialysis bath might be expected to result in alterations in serum calcium concentration, and thereby, of serum PTH levels. Dialysate calcium concentrations throughout this study were maintained at 2.6 meq/liter, and at this level, previous studies have shown that total serum calcium is little effected. 4 Moreover, all patients received phosphate binders in equivalent and constant amounts t h r o u g h o u t the study, thus tending to minimize variations of serum phosphate due to changes in gastrointestinal phosphate absorption. The changes in serum calcium and phosphate observed can probably be attributed to the effect of varying dialysate magnesium levels on PTH secretion and on h o r m o n a l action on bone. The use of high-magnesium dialysis caused a fall in both serum calcium and phosphate, suggesting that bone resorption under these circumstances may have been decreased. The effects of high-magnesium dialysis were evident within the first week of dialysis and continued over the 2 mo of the study. Serum PTH concentration remained elevated but decreased to a lower range. This is comparable to the effects of intravenous infusion of calcium or high-calcium dialysis by means of which P T H levels are also suppressed but do not return to normal values. 5'6 It is of interest that high-magnesium dialysis suppressed P T H secretion without markedly altering serum magnesium levels. Serum magnesium concentrations in all patients were elevated before initiating the study (Table 1), with a mean value of 3.2 meq/liter. It has been demonstrated that dialysate magnesium equilibrated with the ultrafiltrable fraction of serum magnesium, which is considered to be 65~o of the total serum value. 27'28 In the patients studied, mean calculated ultrafiltrable magnesium would be 2.2 meq/liter. The use of 2.5 meq/liter magnesium dialysate concentration would be expected to result, therefore, in a net transfer of magnesium from the bath to the patient and thus in a higher serum magnesium level than was observed. The fate of this transferred magnesium is not known. It is possible, of course, that magnesium may be deposited in soft tissues. The patients dialyzed against a 1.0 meq/liter of magnesium have been shown to have a higher skin magnesium level than those dialyzed against 0.6 meq/liter. 29 Tissue magnesium levels in chronic renal failure have been reported to be normaP ~ or low. 3~ In the latter circumstance, the net transfer of magnesium from dialysis to the patient may be used

628

PLETKA ET AL.

to replete body stores. Moreover, since studies of magnesium balance have not been performed in patients on dialysis, t h e gastrointestinal excretion of magnesium under these circumstances is not known. The use of a low-magnesium dialysate concentration is associated with the return of serum magnesium levels to the normal range, probably by the net transfer of magnesium from the patient to the dialysate fluid. Despite the nearly threefold increase in serum parathyroid h o r m o n e levels that occurred during the first week of low-magnesium dialysis, serum calcium and phosphate concentrations did not increase. The data suggest that the decrease in bone resorption that follows PTH suppression during high-magnesium dialysis is a relatively rapid occurrence. The elevation in P T H concentration secondary to low-magnesium dialysis does not result in increased bone resorption and a subsequent increase in serum calcium and phosphate levels at the same rate. It is possible, therefore, that the lowering of serum magnesium partially interfers with the response of bone to the increased circulating PTH. Recent studies in man have shown that hypomagnesemia was associated with end-organ refractoriness to P T H resulting in hypocalcemia, ~2,~3,~8and that this abnormality may be reversed by magnesium repletion, i~ However, Suh et al. 16'17 suggest that the hypocalcemia in the presence of hypomagnesemia is the result of impaired synthesis or decreased secretion of PTH, Our results are more consistent with end-organ refractoriness, since low magnesium dialysis resulted in a marked rise in serum P T H COncentrations, Furthermore, the serum magnesium concentrations, while lower, were still well above the point where hormone secretion falls. 15 ~7 Although hypomagnesemia per se does not result from low-magnesium dialysis, the sudden decrease of 30~ in serum magnesium concentration may partially and perhaps temporarily blunt the action of PTH on bone. Since serum calcium and phosphate did eventually increase slightly with continued lowmagnesium dialysis, it is possible that low-magnesium dialysis extended over a more prolonged period will result in a greater incidence of secondary hyperparathyroidism. The presence of pruritus in patients adequately dialyzed has been considered a major complication of secondary hyperparathyroidism and one that may require subtotal parathyroidectomy. 32,33 Pruritus has been attributed to elevated serum calcium concentrations, 33 although the increased calcium content of the skin may be a contributory factor. 33 The dramatic and rapid improvement in pruritus following subtotal parathyroidectomy is best explained by a decrease in serum calcium and phosphate concentration, and our findings of alleviation of pruritus with high-magnesium dialysis (and the resultant serum calcium changes) are consistent with this hypothesis. However, the aggrevation of pruritus with low-magnesium dialysis without concomitant increase in serum calcium levels would suggest that other unknown factors may be responsible for this troublesome symptom. The use of a 2.5 meq/liter magnesium dialysate concentration has resulted in a sustained decrease of circulating parathyroid hormone and thus may be a useful method of controlling secondary hyperparathyroidism. However, the use of the 0.5 meq/liter dialysate magnesium concentration, despite its obvious

MAGNESIUM, HYPERPARATHYROIDISM, AND HEMODIALYSIS

629

a d v a n t a g e s in r e d u c i n g s e r u m m a g n e s i u m c o n c e n t r a t i o n s t o a n o r m a l range, m a y result in a m o r e severe h y p e r p a r a t h y r o i d i s m if c o n t i n u e d o v e r l o n g p e r i o d s o f time. A l t h o u g h h i g h - c a l c i u m dialysis as a m e a n s o f s u p p r e s s i n g s e c o n d a r y h y p e r p a r a t h y r o i d i s m in c h r o n i c renal failure has been s u g g e s t e d , t h er e are p o t e n t i a l d a n g e r s o f soft tissue calcification with this m e t h o d o f t r e a t m e n t , especially in t h e p r e s e n c e o f e l e v a t e d s e r u m p h o s p h a t e . T h e r e f o r e , the effectiveness o f h i g h . m a g n e s i u m dialysis on p a r a t h y r o i d f u n c t i o n w o u l d suggest an i m p o r t a n t a l t e r n a t i v e t h e r a p e u t i c a p p r o a c h w h i c h b e ar s f u r t h e r i n v e s t i g a t i o n .

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