Uremic Secondary Hyperparathyroidism Research Articles

Calcimimetics and calcilytics—fooling the calcium receptor

Just a decade after the the calcium-sensing receptor (CaR) was identified, pharmacological manipulation of the CaR is about to enter routine practice. For hyperparathyroid states, calcimimetics, which increase activation of the CaR, have been licensed in Europe and the USA. Calcilytics, which decrease CaR function and increase secretion of parathyroid hormone (PTH), might allow the anabolic effects of PTH on bone to be harnessed for the prevention and treatment of osteoporosis. In a multicentre randomised double-blind placebo-controlled study, Munro Peacock and colleagues recently confirmed the efficacy of the oral calcimimetic cinacalcet for achieving long-term reductions in serum calcium and PTH concentrations in primary hyperparathyroidism (J Clin Endocrinol Metab 2005; 90: 135-41). The arrival of a non-surgical option for this common disorder is important. WHAT NEXT? Study in primary and uraemic secondary hyperparathyroidism will indicate whether the efficacy of calcimimetic agents extends into the longer term. The extracellular relation between the CaR and its ligands and the intracellular signalling cascades that modify PTH gene transcription and secretion need further study. Drugs acting on the CaR might treat other disorders of bone remodelling, including osteoporosis. CaR expression in tissues beyond those involved in mineral ion homoeostasis should remain an important focus of research.

Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients

Secondary hyperparathyroidism is a common complication among long-term dialysis patients. The method of predicting future parathyroid function has not yet been established. Fibroblast growth factor-23 (FGF-23) is a newly found humoral phosphaturic factor. One hundred and three nondiabetic dialysis patients whose plasma intact parathyroid hormone (PTH) levels were below 300 pg/mL were included in the study. Blood samples were stored at -80 degrees C for 2 years. Meanwhile, each physician in charge decided upon the strategy of medical therapy for maintaining intact PTH levels between 150 and 300 pg/mL. Patients were judged 2 years after the sample collection with regard to whether the hyperparathyroidism responded to the medical therapy. The definition of refractory secondary hyperparathyroidism was either (1) retaining intact PTH levels greater than 300 pg/mL 2 years after sample collection, or (2) having received the parathyroid intervention therapy during the observation period. Serum FGF-23 levels were determined with a sandwich enzyme-linked immunosorbent assay system that detects biologically active human FGF-23. Seventeen patients with intact PTH levels greater than 300 pg/mL were judged as having secondary hyperparathyroidism refractory to medical therapy. A stepwise regression analysis revealed that only serum levels of FGF-23 were significantly related to the prognosis of parathyroid function. A receiver-operated characteristic analysis demonstrated that the area under the curves obtained from FGF-23 (7099.9) was significantly greater than that obtained from intact PTH (6306.4, P < .01) and Ca x Pi (5670.3, P <.0001). Although the plasma intact PTH levels at the beginning of the observation period were comparable to each other, the intact PTH levels at 2 years after the sample collection were significantly higher in the patients with FGF-23 >/=7500 ng/L than in those with FGF-23 <7500 ng/L (P < .0001). Serum FGF-23 level was found to be the most useful factor in predicting future development of refractory secondary hyperparathyroidism in long-term dialysis patients with mild secondary hyperparathyroidism. The measurement of serum FGF-23 levels is a promising laboratory examination that can be applied in the clinical practice of uremic secondary hyperparathyroidism.

In brief

Just a decade after the the calcium-sensing receptor (CaR) was identified, pharmacological manipulation of the CaR is about to enter routine practice. For hyperparathyroid states, calcimimetics, which increase activation of the CaR, have been licensed in Europe and the USA. Calcilytics, which decrease CaR function and increase secretion of parathyroid hormone (PTH), might allow the anabolic effects of PTH on bone to be harnessed for the prevention and treatment of osteoporosis.In a multicentre randomised double-blind placebo-controlled study, Munro Peacock and colleagues recently confirmed the efficacy of the oral calcimimetic cinacalcet for achieving long-term reductions in serum calcium and PTH concentrations in primary hyperparathyroidism (J Clin Endocrinol Metab 2005; 90: 135–41). The arrival of a non-surgical option for this common disorder is important.Study in primary and uraemic secondary hyperparathyroidism will indicate whether the efficacy of calcimimetic agents extends into the longer term. The extracellular relation between the CaR and its ligands and the intracellular signalling cascades that modify PTH gene transcription and secretion need further study. Drugs acting on the CaR might treat other disorders of bone remodelling, including osteoporosis. CaR expression in tissues beyond those involved in mineral ion homoeostasis should remain an important focus of research.

Pathogenesis of uremic secondary hyperparathyroidism

It has been assumed that uremic parathyroid hyperplasia predominantly involves generalized polyclonal cellular proliferation, because of multigland involvement. However, the majority of uremic hyperplasias resected from patients with secondary hyperparathyroidism are monoclonal. The specific acquired genetic abnormalities would have a great role in providing this selective advantage of the parathyroid hyperplasia.

Clinical Effect of Intravenous Calcitriol Administration on Secondary Hyperparathyroidism

Background/Aims: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. Method: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 µg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. Results: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, –7.8% in the 1-µg group, –18.9% in the 1.5-µg group and –24.1% in the 2-µg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were –0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-µg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-µg group among the three calcitriol groups. Conclusion: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 µg per dialysis session.

Calcimimetic agents and the calcium-sensing receptor.

Blood ionized extracellular calcium is closely regulated. To accomplish this, a hormone-like receptor that is responsive to extracellular ionized calcium regulates both the secretion of parathyroid hormone and the excretion of urinary calcium (as well as other cellular processes). Several hereditary disorders have mutations that cause either loss or gain of function of the calcium-sensing receptor, and alterations of the calcium-sensing receptor may play a role in both primary and secondary hyperparathyroidism. Calcimimetics are agents that act to make the calcium-sensing receptor more sensitive to extracellular ionized calcium; thereby they suppress the secretion of parathyroid hormone. Early trials in animal models of secondary hyperparathyroidism and in patients with primary hyperparathyroidism or with uremic secondary hyperparathyroidism have shown that the first generation calcimimetic, R-568, effectively lowers parathyroid hormone levels and is well tolerated.

Race is a major determinant of secondary hyperparathyroidism in uremic patients.

In the general population, blacks have higher parathyroid gland mass and circulating parathyroid hormone (PTH) levels than whites. This may predispose black patients to more severe parathyroid disease when renal failure develops. Therefore, racial differences in the severity of uremic hyperparathyroidism were examined in a population of patients with end-stage renal disease (ESRD). Among ESRD patients receiving hemodialysis or peritoneal dialysis, two or more values of intact PTH (immunoradiometric assay, pg/ml) obtained at least 90 d apart were available in 1270 prevalent cases (61.1% blacks, 51% males, and 31.1% diabetic), including 466 incident cases with onset of ESRD after 1993. Maximum PTH levels were analyzed as a function of race, gender, age, diabetic status, and levels of serum calcium, phosphorus, alkaline phosphatase, and aluminum. Using a stepwise multiple regression model, the determinants of maximum PTH in the order of their importance were black race, serum phosphorus, absence of diabetes, younger age, serum calcium, and female gender. The maximum PTH levels averaged 641.7 in blacks and 346.0 in whites after adjusting for age, gender, diabetic status, serum calcium, and phosphorus (P < 0.0001). In blacks compared with whites, the odds ratio (95% confidence interval) for adynamic bone disease (maximum PTH <150 pg/ml) was 0.26 (0.17 to 0.41), whereas the odds ratio for hyperparathyroid bone disease (mean PTH >500 pg/ml) was 4.4 (2.10 to 9.25). Race is a major independent determinant of uremic secondary hyperparathyroidism. Among ESRD patients, blacks may be at an increased risk for hyperparathyroid bone disease and whites for adynamic bone disease.

The role of calcium-sensing receptor abnormality in the pathogenesis of secondary hyperparathyroidism.

because the nodular lesion is at an advanced stage of Introduction parathyroid hyperplasia. In order to elucidate the relationship of CaR and 2In uraemic secondary hyperparathyroidism (2-HPT), HPT more precisely, the expression of CaR mRNA a normal serum calcium (Ca) does not adequately and protein was studied in surgically resected parasuppress excessive parathyroid hormone (PTH) prothyroid glands of six patients with severe 2-HPT (intact duction and secretion [1]. This result suggests an PTH>800 pg/ml ) on haemodialysis. Light microscopy abnormal Ca-sensing mechanism in 2-HPT. The sensitshowed that all glands included hypertrophic and ivity of the parathyroid to extracellular Ca has been hyperplastic lesions with or without nodular change. evaluated by the sigmoidal curve between serum intact Immunohistological examination demonstrated the PTH and Ca concentrations [2]. Although there is decreased expression of CaR protein in all hyperplastic controversy that the set-point Ca concentration calcuparathyroid glands tissues, in particular in nodular lated from this curve precisely reflects the sensitivity hyperplastic lesions compared with diffuse lesions. In of the parathyroid cell for Ca [3–5], the depressed addition, the expression of CaR mRNA by quantitative sensitivity for Ca has been clearly shown in vitro and RT–PCR and Northern blotting analyses showed a by the common experience in severe 2-HPT that high PTH develops despite the unphysiological hypercalcaemore profound reduction in large nodular hyperplastic mia. The mechanism for this abnormality has been parathyroid glands compared to that in small hyperplpartially explained by decreased plasma-activated vitastic parathyroid glands. The finding that the expresamin D, an increased parathyroid cellular mass, or a sion of parathyroid gland CaR mRNA and protein reduced vitamin D receptor in the parathyroid gland. decreases particularly in large nodular hyperplastic However, the precise mechanism is not yet fully glands is consistent with the results of two previous understood. reports. We next evaluated the correlation between resected gland weight and the expression of CaR mRNA, which Ca-sensing receptor in 2-HPT was classified into four grades by mRNA density. A significant inverse correlation was observed between Since the discovery of the Ca-sensing receptor (CaR) the weight and CaR mRNA of resected parathyroid in bovine [6 ] and human parathyroid [7], much attenglands. tion has been directed at the relationship between CaR Parathyroid cells in nodular hyperplasia generally and abnormal sensitivity for Ca in 2-HPT. Kifor et al. show a greater proliferative change compared with first reported the decreased expression of CaR protein those in diffuse hyperplasia [11]. Therefore, the relation in parathyroid tissue [8]. This finding was also supbetween proliferative activity and CaR protein expresported by CaR mRNA levels [9]. sion in the parathyroid cell was examined. Proliferation These two reports together demonstrate that the was determined by proliferative cellular nuclear antigen downregulation of CaR is more remarkable in nodular (PCNA) staining. CaR protein was strongly expressed hyperplastic lesions of the parathyroid compared with in parathyroid tissue where the PCNA staining was that in diffuse lesions and that the same downregulation scarce. In contrast, CaR expression was rare in tissue is observed in the hyperplastic tissue of primary hyperwhere the PCNA was strongly stained. These results parathyroidism. Since hyperplastic parathyroid glands suggest that the proliferative potential of parathyroid display less sensitivity to Ca [10], it appears to be tissue inversely correlates with CaR expression and reasonable that CaR expression and the sensitivity for sensitivity for Ca. Ca are suppressed more in nodular hyperplastic glands, The relation between cell proliferation and expression of CaR is similar to that between cell proliferation Correspondence and offprint requests to: Tadao Akizawa, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227, Japan. and vitamin D receptor density [12]. Expression of

Calcium-sensing by parathyroid glands in secondary hyperparathyroidism.

Calcium-sensing by the parathyroids is abnormal in familial benign hypocalciuric hypercalcemia and in primary hyperparathyroidism (primary HPT), but the role of a calcium-sensing defect in uremic secondary hyperparathyroidism (secondary HPT) remains controversial. To study the regulation of PTH release by calcium, set point estimates were obtained using the four parameter model during in vivo dynamic tests of parathyroid gland function in 31 patients with secondary HPT, 8 patients with advanced secondary HPT studied shortly before undergoing parathyroidectomy (Pre-PTX), 3 patients with primary HPT, and 20 subjects with normal renal function (NL); the response to 2-h i.v. calcium infusions was also evaluated. Neither blood ionized calcium (iCa+2) levels nor the set point for calcium-regulated PTH release differed between secondary HPT and NL; iCa+2 levels and set point values were moderately elevated in Pre-PTX and markedly elevated in primary HPT. Compared with values obtained in NL, the lowest serum PTH levels achieved during calcium infusions, expressed as a percentage of pre-infusion values, were incrementally greater in secondary HPT, Pre-PTX, and primary HPT, whereas the slope of the relationship between iCa+2 and PTH, expressed as the natural logarithm (ln) of percent preinfusion values, decreased incrementally in secondary HPT, Pre-PTX, and primary HPT. The inhibitory effect of calcium on PTH release is blunted both in secondary HPT and primary HPT because of increases in parathyroid gland mass, but a calcium-sensing defect is a late, rather than early, consequence of renal secondary HPT.

A Structural Approach to Renal Bone Disease

A Structural Approach to Renal Bone Disease

In vivo assessments of calcium-regulated parathyroid hormone release in secondary hyperparathyroidism

In vivo dynamic tests of parathyroid gland function have provided useful information about the secretory behavior of parathyroids in various clinical disorders, but the limitations of this approach must be recognized when applied to studies of parathyroid gland physiology. Set point abnormalities have been documented in vivo both in primary hyperparathyroidism and in familial hypocalciuric hypercalcemia. Such findings are consistent with in vitro results obtained in studies of dispersed parathyroid cells from patients with primary hyperparathyroidism and with recently described alteration in calcium receptor expression in patients with FHH. The assessment of parathyroid gland function in patients with end-stage renal disease presents distinct methodological problems, however, because of marked variation in the degree of parathyroid gland enlargement. Neither the four parameter model originally used to describe set point abnormalities both in vitro and in vivo or alternative approaches to the assessment of PTH secretion in vivo adequately address this important issue. Results from recent in vivo studies of patients with chronic renal failure do not support the view that the set point for calcium-regulated PTH release is abnormal in secondary hyperparathyroidism or that treatment with calcitriol lowers the set point for calcium-regulated PTH release in patients with uremic secondary hyperparathyroidism. The concept of set point disturbances has strongly influenced discussions about the pathogenesis of secondary hyperparathyroidism, and it has served as a focal point for examining the therapeutic response to calcitriol in patients with this disorder. This matter requires careful reconsideration, however, in light of recent clinical findings and the development of techniques to directly assess the molecular mechanisms responsible for regulating calcium-mediated PTH release in renal failure and other disorders of mineral metabolism. Although knowledge in this area remains limited, the extent of parathyroid hyperplasia and the role of factors that influence the development of parathyroid gland enlargement may ultimately prove to be particularly important modifiers of parathyroid gland function in chronic renal failure.

Non-suppressible parathyroid hormone secretion is related to gland size in uremic secondary hyperparathyroidism

To determine the relative importance of parathyroid gland enlargement and alterations in calcium sensing (set-point changes) in the pathogenesis of uremic secondary hyperparathyroidism (2 degrees HPT), we investigated the relationship between estimates of parathyroid gland size and calcium-mediated parathyroid hormone (PTH) suppression in 19 normocalcemic 2 degrees HPT patients on chronic maintenance hemodialysis. We compared our results to calcium-mediated PTH suppression in 12 normal volunteers, 12 patients with familial benign hypocalciuric hypercalcemia (FBHH), a disorder of abnormal calcium sensing, and 9 subjects with primary hyperparathyroidism (1 degree HPT), which is characterized by both calcium set-point abnormalities and parathyroid gland enlargement. We found that the 2 degrees HPT group displayed a distinctive pattern of calcium-mediated PTH suppression characterized by a failure to normally suppress PTH at supraphysiologic ionized calcium concentrations, similar to 1 degree HPT, but without the rightward shift of the calcium-PTH suppression curve that characterizes calcium sensing abnormalities in FBHH and 1 degree HPT. In the patients with 2 degrees HPT, hypercalcemic suppression resulted in an ending PTH (as a percent of baseline) that was significantly higher (39.8 +/- 4.47%), and a slope of the calcium-PTH suppression curve that was significantly less negative (-4.8 +/- 0.53), compared to respective values of 19.4 +/- 1.81% (P = 0.0009) and -9.0 +/- 1.02 (P = 0.001) in normals and 19.1 +/- 2.49% (P = 0.001) and -9.6 +/- 1.11 (P = 0.0006) in FBHH. Values of ending PTH and slope in 2 degrees HPT patients, however, were similar to those found in 1 degree HPT (49.8 +/- 6.35%, P = 0.21 and -4.5 +/- 0.74, P = 0.72). The ionized calcium concentration required to attain half maximal PTH suppression (EC50) in 2 degrees HPT (1.20 +/- 0.02 mmol/liter) was not significantly different from normals (1.25 +/- 0.01 mmol/liter, P = 0.12) but was significantly less than in 1 degree HPT (1.52 +/- 0.02 mmol/liter, P < 0.0001) and in FBHH (1.44 +/- 0.02 mmol/liter, P < 0.0001). More importantly, we found a significant linear correlation between the natural logarithm of gland size and ending PTH suppression (r = 0.71, P < 0.001) and slope of the calcium-PTH curve (r = 0.67, P = 0.002) in 2 degrees HPT. Thus, calcium non-suppressible PTH secretion in 2 degrees HPT does not represent a simple set-point error, but rather correlates with the degree of parathyroid gland enlargement.

Effects of new vitamin D analogues on parathyroid function in chronically uraemic rats with secondary hyperparathyroidism

Treatment with calcitriol or its analogue, alfacalcidol often leads to hypercalcaemia, hyperphosphataemia or both in patients which chronic renal failure and advanced secondary hyperparathyroidism. We tested three new vitamin D analogues (CB 1093, EB 1213, GS 1725) in an attempt to identify potentially non hypercalcaemic compounds, capable of decreasing plasma parathyroid hormone (PTH) concentration. Male Wistar AF rats aged 12-14 weeks were fed a synthetic, phosphate-rich diet and underwent either sham surgery (control) or a standard two-step 5/6th nephrectomy. Four weeks later, renal function was mildly decreased in the latter. Chronic renal failure rats were then divided into six groups, with 8-10 rats in each group. They received daily 1.p. injections, from days 0 to 4, of either placebo, calcitriol, or one of the following three active vitamin D analogues: CB1093, 0.25 micrograms; EB1213, 0.25 or 1.25 micrograms; and GS1725, 0.025 micrograms/kg body weight per day, respectively. Sham-operated rats received no drug. On day 5, arterial blood was sampled and rats were sacrificed. At predefined dosage schedules, all three compounds significantly decreased plasma immunoreactive PTH levels (except EB1213 at low dose). The decrement was somewhat less marked than that obtained with calcitriol, at the dose of 0.25 micrograms/kg b.w. per day. However, calcitriol induced a marked increase in plasma calcium and phosphate concentrations at that dose, whereas vitamin D analogues led to a more modest increase in plasma calcium level, and none to a worsening of hyperphosphataemia. CB1093 treatment was even associated with a significant decrease in plasma phosphate level. All three calcitriol analogues tested are promising as non-hypercalcaemic agents in the treatment of uraemic secondary hyperparathyroidism. However, more prolonged administration to uraemic rats of calcitriol analogues with slightly modified dosage schedules and of calcitriol with lower non-hypercalcaemic dose is required for an optimal comparison before considering clinical trials.

Calcitriol in the management of secondary hyperparathyroidism of renal failure.

Secondary hyperparathyroidism (HPT) is characterized by persistent hypersecretion of parathyroid hormone (PTH), and produces characteristics of hyperparathyroid bone disease and a variety of biochemical and hormonal derangements. Management of uremic secondary HPT involves both prevention and treatment. Among preventive measures are attempts to control serum phosphate and serum calcium concentrations through dietary restriction, administration of phosphate binders, and calcium supplementation. Treatment with a vitamin D analog such as calcitriol returns plasma calcium concentrations toward normal and suppresses PTH secretion. The availability of a parenteral formulation of calcitriol, and new information regarding alternative routes of administration and regimens employing oral pulse dosing have renewed interest in calcitriol for the management of uremic secondary HPT.

X-ray microanalysis of elemental changes in human parathyroid glands in primary and secondary hyperparathyroidism.

The elemental composition of chief cells of parathyroid glands from patients with adenomatous primary hyperparathyroidism (HPT) and uremic secondary HPT was studied by X-ray microanalysis. Glands histologically deemed normal were used as controls. The analyses were also carried out on tissue specimens incubated in hypo-, normo- and hypercalcemic media (0.5, 1.25, and 3.0 mM calcium concentration). Analysis of chief cells from normal glands did not reveal any significant differences in ionic composition after exposure to the different calcium concentrations. In chief cells from adenomatous and uremic hyperplastic glands, elemental changes were noted. In comparison with specimens incubated in 1.25 mM calcium medium, cells in 0.5 mM calcium medium had a lower content of potassium and phosphorus. After stimulation with increasing extracellular concentration, an increase in the K/Na ratio was observed, due to a marked decrease of sodium and an increase of potassium; the calcium concentration was almost unchanged. Our findings indicate that in HPT an increase in serum calcium concentration might exert a stimulatory effect on the Na/K pump (sodium pump) and on the calcium-activated potassium channels. Either of these mechanisms might contribute to a lowering of cytoplasmic calcium. Our observations suggest that changes in ionic content of the parathyroid cells may be of importance for the stimulus secretion process in the cells.

Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism

Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism

CLINICAL REVIEW 20 Recent Advances in the Pathogenesis and Therapy of Uremic Secondary Hyperparathyroidism

THE association of renal failure with metabolic bone disease has been recognized since the time of Albright. The term “renal osteodystrophy” is not specific. It encompasses the lesions of osteitis fibrosa, osteomalacia, mixed lesions, osteoporosis, and growth retardation. The histological features of osteitis fibrosa include osteoclastosis, increased bone resorption, and marrow fibrosis. In addition, osteoblastic activity is increased with an abnormally large percent of bone surface involved in bone formation. This state of high bone turnover is also characterized by increased quantities of woven osteoid. It differs from normal lamellar osteoid in that there is a haphazard arrangement of collagen fibers. Although woven osteoid can be mineralized, the calcium is deposited as amorphous calcium-phosphate instead of hydroxyapatite. It is clear that osteitis fibrosa (and probably other uremic derangements) is the result of excessive secretion of PTH. With the advent of effective dialysis therapy, it is now com...

Total parathyroidectomy and autogenous parathyroid graft placement for treatment of hyperparathyroidism due to chronic renal failure

We treated 33 patients with chronic renal insufficiency and severe hyperparathyroidism with total parathyroidectomy and placement of an autogenous parathyroid graft in the forearm musculature. Postoperative biochemical data, symptomatic data, or both were available in 28 of the patients, of whom all but 1 showed evidence of improvement. Immunoreactive parathyroid hormone studies were made from 9 to 52 months postoperatively in 22 patients. Background immunoreactive parathyroid hormone levels markedly decreased after surgery and were in the optimum range in 18 patients. In the other four patients, immunoreactive parathyroid hormone levels remained above the optimum range, but in only one of the four did symptoms and biochemical parameters fail to improve. Gradients for immunoreactive parathyroid hormone across the forearm musculature were demonstrable in 18 of 22 patients, which proved the secretory function of the graft. One patient required resection of a portion of the grafted tissue on two occasions because of recurrent hypercalcemia. The technique of total parathyroidectomy and autogenous parathyroid grafting seems to be a valid alternative to subtotal parathyroidectomy for the treatment of uremic secondary hyperparathyroidism.