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J Am Soc Nephrol 14:407-414, 2003
© 2003 American Society of Nephrology

PTH Pulsatility but Not Calcium Sensitivity Is Restored after Total Parathyroidectomy with Heterotopic Autotransplantation

Claus P. Schmitt*, Swee Löcken*, Otto Mehls*, Johannes D. Veldhuis§, Thomas Lehnert{dagger}, Eberhard Ritz{ddagger} and Franz Schaefer*

Departments of *Pediatrics, {ddagger}Internal Medicine, and {dagger}Surgery, University of Heidelberg, Heidelberg, Germany, and §Department of Internal Medicine, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, Minnesota.

Correspondence to Dr. Franz Schaefer, Division of Pediatric Nephrology, University Children’s Hospital, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. Phone: 49-6221-56-32396; Fax: 49-6221-56-4203;


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. In healthy humans, parathyroid hormone (PTH) is secreted via basal mode with superimposed oscillatory bursts every 8 to 12 min. Amplitude and frequency changes mediate the instantaneous response of the parathyroids to changes in ambient Ca2+ concentrations. The parathyroid gland tetrad may be synchronized by autonomic innervation. This study investigated the effect of total parathyroidectomy and heterotopic autotransplantation of parathyroid tissue (PTX) on PTH secretion patterns in nine patients with end-stage renal disease. Intact-PTH versus time concentration profiles were obtained early (1 to 8 wk, n = 4) or late (15 to 33 mo, n = 5) after PTX. In four patients late after PTX, Ca2+ responsiveness of PTH secretion was additionally investigated by citrate and calcium clamp studies. The nonrandomness of plasma PTH fluctuations was assessed by the approximate entropy (ApEn) statistic, and secretion characteristics by multiparametric deconvolution analysis. Results were compared with those of matched normal subjects and chronic renal failure (CRF) patients without PTX. PTH burst frequency was 2.9 ± 0.1 h-1 early and 7 ± 0.4 h-1 late after PTX as compared with 8.1 ± 0.4 h-1 in CRF and 7 ± 0.3 h-1 in healthy controls. Fractional pulsatile PTH secretion was diminished after PTX (18 ± 2%) compared with healthy controls (32 ± 5%, P < 0.05) and CRF patients (25 ± 4%, P = 0.05). The orderliness of PTH release was significantly reduced after PTX (ApEn: 1.59 ± 0.03 versus 1.41 ± 0.09 in healthy and 1.46 ± 0.03 in CRF controls, P < 0.01). Acute hypocalcemia elicited a lesser increase in pulsatile PTH secretion in PTX patients (147 ± 134%) than in the CRF (500 ± 92%, P = 0.05) and healthy controls (1410 ± 290%, P < 0.05), mainly due to a diminished mass of PTH secreted per burst. Pulsatile PTH secretion was also resistant to hypercalcemia, wherein the suppression of burst mass was significantly reduced compared with that in healthy controls. In conclusion, pulsatile PTH secretion is partially restored within 2 yr of PTX. However, the capacity of the autotransplanted tissue to adapt to changes in ionized calcium remains profoundly disturbed. E-Mail: franz_schaefer@med.uni-heidelberg.de


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Oscillatory secretion typifies most peptide hormone systems. This episodic mode of signaling may optimize the efficacy of hormone-receptor interaction and cellular responses (1,2). A pulsatile secretion, accounting for at least 30% of total hormone release, also characterizes PTH release (3). The immediate homeostatic response of the parathyroid to changes in ionized calcium concentrations is encoded by modulation of the amplitude and in lesser measure the frequency of PTH pulses (3). Secondary hyperparathyroidism of CRF is associated with distinct changes of PTH control: (1) augmentations of PTH burst mass and tonic secretion; (2) increased PTH pulse frequency; and (3) reduced adaptations of pulsatile PTH release to variations in ionized calcium (4).

The mechanism underlying the generation of synchronous PTH pulses by the spatially separated parathyroid glands is unknown. Both the thyroid and parathyroid glands are densely innervated by sympathetic, parasympathetic, and sensory nerve fibers (5,6). Sympathetic fibers reaching the parathyroids originate in the superior cervical ganglion, and vagal fibers from the dorsal motor nucleus project via the thyroid and inferior laryngeal nerves to intraparathyroidal cholinergic ganglia. Nerve endings extend into the endocrine cell parenchyma, where both adrenergic and cholinergic receptors are present (7,8). Whereas parasympathetic input inhibits basal and calcium-responsive PTH secretion (9), the sympathetic nervous system exerts either stimulatory and inhibitory effects via {beta}- and {alpha}-adrenergic receptors, respectively (10). PTH affects sympathetic neurotransmission in the SCG (11) and cholinergic activity in intraparathyroidal ganglia and nerve terminals (12), providing the basis for a neuroendocrine feedback system. A plausible notion is that the autonomic nervous system influences ultradian oscillatory secretion of PTH.

An opportunity to investigate the mechanisms subserving synchronous PTH secretion in humans is given by the surgical procedure of total parathyroidectomy with autotransplantation of parathyroid fragments. We reasoned that immediately after surgery, autotransplanted parathyroideal cells would secrete PTH largely independently of neuronal control, possibly without well-organized oscillations. This disruption might be overcome when autotransplanted parathyroid glands are reinnervated (13). To test this thesis, we investigated spontaneous PTH secretion in patients with end-stage renal disease (ESRD) either within the first 8 wk or after more than 1 yr after total PTX with autotransplantation. Concomitantly, we analyzed calcium sensitivity of the autotransplanted tissue using the sodium citrate/calcium gluconate clamp technique. Results were compared with findings in ESRD patients without PTX and healthy controls (3,4).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
PTX Patients
Eight ESRD patients (6 men, 2 women), participated in the study (Table 1). The patients’ mean age was 49 (range, 21 to 68) years. Underlying diseases included autosomal dominant polycystic kidney disease (n = 2), reflux nephropathy (n = 2), chronic glomerulonephritis (n = 2), bilateral renal hypoplasia, and gout nephropathy. Mean duration of ESRD was 7.9 (range, 0.2 to 22) years. All subjects had undergone total PTX and autotransplantation of a parathyroid tissue fragment in the abdominal subcutaneous tissue.


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  		Table 1. Biochemical characteristics of eight patients after PTXa
 
Four patients were studied within 8 wk of PTX, and five patients 15 to 33 mo after surgery. One patient was studied in both the early and the late postsurgical period (Table 1). Five patients were on hemodialysis for a weekly dialysis time of 12 to 18 h. Only one of these had significant residual renal function. Three patients had undergone renal transplantion 4, 26, and 72 mo before the study and had developed chronic allograft dysfunction with moderate chronic renal failure (GFR: 25 [range, 18 to 45] ml/min per 1.73 m2). The patients’ basic biochemical characteristics are given in Table 1. Mean 25 (OH)2D3 plasma levels were 79 (range, 20 to 236) nmol/L, mean 1,25(OH)2D3 plasma levels were 25 (range, 12 to 44) ng/L. Treatment with calcitriol was withheld for at least 2 d, and 25-OH-vitamin D3 for at least 1 wk before the study. Other chronic medication, including diuretics, calcium channel blockers, {alpha}-adrenergic and {beta}-adrenergic antagonists, angiotensin-converting enzyme inhibitors, phosphate binders, and sodium bicarbonate were withheld at the morning of the study day. Hence, the only medication continued on the study day was maintenance immunosuppression in the posttransplantation patients (cyclosporine A in two, methylprednisolone in three, mycophenolate mofetil in one, and tacrolimus in one patient). Ultrasonography was performed at the time of investigation to exclude local recurrence of parathyroid adenoma.

Controls
Nine healthy subjects and nine patients with CRF served as controls (3,4). Both the normal and CRF controls were matched with the PTX patients for age (healthy controls: 34 [range, 21 to 59] yr; CRF controls: 43 [range, 19 to 59] yr) and gender. In addition, the CRF controls were individually matched with the PTX patients with respect to the proportion of HD patients (6 out of 9), and GFR in the patients with compensated CRF (20.3 [range, 12 to 29]). The same study design, standardization procedures, and laboratory and statistical techniques were used in the PTX patients and the controls (3,4).

Study Protocol
The protocol was approved by the local ethical committee, and written informed consent was obtained from each participant. All individuals were advised to ingest their normal diet, refrain from athletic activities, and abstain from caffeine, nicotine, and alcohol at least 24 h before each investigation. The patients remained in fasting conditions for at least 10 h. All subjects underwent ECG monitoring during calcium and citrate infusions.

Studies were performed in the morning between 10 a.m. and 1 p.m. Hemodialysis patients were studied immediately before a regular dialysis session. Two cannulae were inserted into contralateral cubital veins, one for blood sampling at 1 min intervals (1 ml each) and the other for infusion of a corresponding amount of 0.9% NaCl. Samples for plasma PTH were withdrawn over an interval of less than 15 s, centrifuged immediately, and kept frozen at -70°C until assay.

Calcium gluconate and sodium citrate clamp studies were performed 1 wk apart in randomized order in four patients 16 to 33 mo post-PTX. One session comprised a 75-min baseline blood-sampling period followed by sodium citrate infusion to induce hypocalcemia; in the other session, the baseline period was followed by calcium gluconate infusion to achieve hypercalcemia. Ca2+ was measured online at 10-min intervals during the normocalcemic periods, and at 5-min intervals during the periods of hypo- and hypercalcemia.

Citrate Clamp.
After a baseline observation period of 75 min, sodium citrate was infused at rates of 0.6 mmol/kg · h, 0.4 mmol/kg · h, and 0.35 mmol/kg · h, respectively, in sequential 10-min intervals, aiming for 0.2 mmol/L decrease in Ca2+. Thereafter, steady-state hypocalcemia was maintained for 75 min by infusing 0.3 mmol/kg · h sodium citrate. Ca2+ decreased by 0.17 ± 0.03 mmol/L during the first 30 min of citrate infusion and remained stable during 75 min of maintenance infusion.

Calcium Clamp.
After a baseline observation period of 75 min, hypercalcemia was established by infusing calcium gluconate at a dose of 0.15 mmol/kg · h for 30 min (targeted Ca2+ increase: 0.2 mmol/L). Steady-state hypercalcemia was maintained for 75 min by continuous infusion of 0.05 mmol/kg · h calcium gluconate. Ca2+ concentrations increased by 0.21 ± 0.03 mmol/L during the first 30 min and remained stable during the maintenance infusion. Identical calcium kinetics were achieved in post-PTX patients and in the CRF controls without PTX. In patients who did not take part in the clamp study, the baseline period was extended to 120 min.

Assays
Intact PTH was measured using a two-site immunoradiometric assay (Allégro; Nichols, San Juan Capistrano, CA) with a sensitivity of 0.1 pmol/L. All samples from an individual were measured in duplicate in the same assay. The mean intra-assay coefficient of variation (CV) was 4.7%, the inter-assay CV 5.5%. An ion-selective electrode system was used to determine blood Ca2+ concentrations (Ionometer EH-F; Fresenius, Oberursel, Germany). The results were corrected for pH 7.4. The mean intra-assay and inter-assay CV of Ca2+ measurements was <1.5%.

Analysis of Plasma PTH Half-Life
In the four patients who underwent a calcium clamp investigation, the subject-specific PTH disappearance half-life was measured during the initial phase of hypercalcemia. During this period, plasma PTH concentrations declined in an exponential fashion to a new detectable steady-state. To allow for persistent residual secretion of PTH, the plasma PTH concentration time series were fitted to a decay model allowing for admixed baseline secretion as described earlier (3). In subjects in whom a hypercalcemic clamp was not performed, the PTH half-life was derived from its relationship to GFR obtained in a previous calcium clamp study in 13 patients with CRF (4).

Deconvolution Analysis
The plasma PTH concentration profiles obtained by 1 min sampling were analyzed by multiparameter deconvolution (14). This model assumes that plasma PTH concentrations are determined jointly by five correlated parameters: (1) a finite number of discrete secretory bursts occurring at specific times, and having (2) individual amplitudes (maximal rate of secretion attained within a burst), (3) a common half-duration (duration of an algebraically Gaussian secretory pulse at half-maximal amplitude), with pulses superimposed on a (4) basal time-invariant PTH secretory rate, and (5) a subject-specific monoexponential plasma PTH half-life. To verify potential pulses, pulse amplitude was required to exceed the 95% joint experimental nonlinear asymmetric confidence intervals (15). The fitting pathways used here were validated earlier for GH and insulin using computer-synthesized and hormone-injected true-positive pulses (16,17).

The following parameters were estimated under each study condition: number, locations, amplitudes, and half-duration of PTH secretory bursts; mass of hormone secreted per burst. and a nonnegative maximal basal (tonic) PTH secretion rate. The pulsatile secretion rate is the product of the number of secretory events and the mean mass of hormone secreted per burst. The tonic hormone secretion rate reflects the maximal nonpulsatile component. Total hormone secretion is the sum of tonic and pulsatile secretion.

Approximate Entropy Statistic
The scale- and model-independent approximate entropy statistic (ApEn) quantitates regularity (orderliness) of fluctuations in a given hormone time series (18,19). This measure represents the negative logarithm of the summed probability that any given particular pattern length of m consecutive points will be repeated within a tolerance or distance r on next incremental comparison. Here, m was set at 1, and r at 0.2 (20%) of the PTH series SD, which serves to normalize ApEn against different absolute PTH concentrations (20). Previous theoretical analyses and clinical applications have demonstrated that these input parameters produce good statistical validity for ApEn values (18,19,21,22). ApEn values typically lie between zero (perfectly ordered) and 2 to 3 (highly random). Typically 30 or more sequential observations afford reliable estimation of the ApEn.

Descriptive Statistics
Kruskal-Wallis one-way ANOVA on ranks was used to assess distinctions between secretion parameters between the PTX and control groups, followed by all pairwise multiple comparison procedure (Dunn’s method) to contrast means. The Mann-Whitney rank sum test was used for comparison of two groups. To assess within-group differences induced by calcium and citrate clamping, a repeated measure ANOVA on ranks was performed, followed by all pairwise multiple comparison procedures (Dunnett’s method). Data are given as means ± SEM. In the patients participating in both clamp studies, the mean of the two baseline periods was calculated to express normocalcemic PTH secretion parameters. None of the secretory characteristics showed a significant difference between baseline investigations.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PTH Pulse Frequency and Orderliness of Release during Normocalcemia
In the PTH concentration versus time profiles obtained within the first 2 mo after PTX, few erratic pulses at a frequency of 2.5 to 3 bursts per hour could be detected (Table 2, Figure 1). In the five patients investigated 15 to 33 mo after PTX, pulse frequency was greater at 6.2 to 8.6 h-1. The mean PTH pulse frequency in all PTX patients combined (5.7 ± 0.6 h-1) was slightly lower compared with that in healthy controls and significantly lower compared with CRF patients without PTX (Table 2). ApEn was high in the first 2 mo after PTX; i.e., the orderliness of PTH patterns was significantly reduced (1.61 to 1.73) compared with that in patients studied later after PTX (1.41 to 1.63). However, even in this late post-PTX phase, PTH orderliness remained less than that observed in healthy subjects (0.37 to 1.58, P < 0.05) and tended to be lower than that of CRF controls with intact parathyroids (1.35 to 1.63, P = NS).


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  		Table 2. Characteristics of baseline PTH secretion under normocalcemia
 


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  		Figure 1. Representative plasma PTH concentration versus time profiles (mean ± SD of duplicate measurements, upper panels) and corresponding calculated PTH secretion rates (lower panels) in a patient 48 h after PTX (left) and in the same patient 16 m later (right).

 
Parathyroid Mass–Dependent PTH Secretory Characteristics
In the three PTH concentration versus time profiles obtained during the first 5 wk post-PTX, the calculated PTH mass released per burst was very low (0.3, 0.45, and 0.57 pmol/L), contributing only 7, 11, and 14% to total PTH secretion (Figure 2). The single patient investigated 2 mo post-PTX exhibited three much larger pulses (mean PTH mass per burst: 6.4 pmol/L) accounting for 30% of total PTH release. In patients studied late after PTX, PTH burst mass was consistently increased compared with very early post-PTX patients, and similar to the healthy controls (Table 2). The burst frequency was also comparable; therefore, the pulsatile PTH secretion rate in the late post-PTX group was similar to the healthy controls. However, mean PTH concentrations were threefold elevated over normal, due to a twofold elevation of plasma PTH half-life (5.4 ± 0.8 versus 2.5 ± 0.1 min, P < 0.05) and to a relatively higher tonic (non-pulsatile) PTH secretion (68 ± 12 versus 35 ± 4 pmol/L · h, P < 0.05). Overall, the pulsatile release mode contributed a smaller fraction to total PTH secretion in the post-PTX patients (18 ± 2%) than in the CRF (25 ± 4%, P = 0.05) and the normal controls (32 ± 5%, P < 0.05).



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  		Figure 2. Plasma PTH concentration curve during a sodium citrate clamp in a healthy volunteer (upper panel) and a CRF patient (same as shown in Figure 1) studied 16 mo after PTX (lower panel).

 
PTH Secretion during Hypocalcemic Clamp
Plasma PTH concentrations increased during induction of hypocalcemia (first 30 min of sodium citratre infusion) by 24 ± 23% in the post-PTX patients (P = NS). This response was much weaker than that in healthy individuals (+317 ± 53%, P < 0.05) and non-PTX CRF patients (+106 ± 26%, P < 0.05). During steady-state hypocalcemia, mean plasma PTH returned to baseline levels in PTX patients (108 ± 14% of baseline). However, mean PTH remained elevated at 170 ± 18% (P < 0.05) of baseline in non-PTX patients and 186 ± 27% (P < 0.05) in healthy controls. While the acute decline in plasma Ca2+ was counteracted in healthy and CRF controls by a prompt and selective rise in pulsatile secretion of 1410 ± 290% and 500 ± 92%, respectively, this response was largely absent in the patients after PTX (+147 ± 134%, P < 0.05 versus healthy; P = 0.05 versus CRF controls). PTH burst frequency increased by only 49 ± 20% (P < 0.05 versus baseline), and PTH burst mass by only 47 ± 73% (P = NS) in PTX patients. Changes were much more pronounced in both control groups (Figure 3). Tonic PTH secretion was not different (PTX, +4 ± 16%; non-PTX patients, +10 ± 13%; healthy controls, +210 ± 172%; P = NS). During steady-state hypocalcemia, tonic PTH secretion increased in CRF patients (54 ± 28% over baseline, P < 0.05) and in healthy controls (213 ± 30%, P < 0.05), but not in the patients after PTX (+4 ± 16%).



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  		Figure 3. Fractional (percentage) responses for discrete PTH secretion parameters to hypocalcemia (upper panels) and hypercalcemia (lower panels) in 4 CRF patients after PTX (triangle), 9 CRF patients without PTX (rhombus), and in 9 healthy controls (circle). * P < 0.05 versus healthy controls; $ P < 0.05 versus non-PTX CRF controls.

 
Orderliness of pulsatile PTH release increased significantly in healthy controls during steady-state hypocalcemia (1.21 ± 0.11 versus 1.37 ± 0.13 during normocalcemia, P < 0.05); the same tendency was observed in the PTX patients (ApEn, 1.46 ± 0.03 versus 1.53 ± 0.05) and in non-PTX CRF controls (1.39 ± 0.05 versus 1.49 ± 0.03).

PTH Secretion during Hypercalcemic Clamp
In the post-PTX patients, hypercalcemia induced an immediate, exponential decline in plasma PTH levels to a new steady-state 59 ± 14% below baseline (P = NS). PTH oscillations were largely absent during hypercalcemia, but they reappeared when plasma PTH concentrations had reached a new steady-state. PTH pulse frequency was not substantially changed in PTX (14 ± 9%, P = NS) and CRF patients (+2 ± 7%, P = NS). However pulse frequency was 25 ± 7% lower than baseline in healthy controls (P < 0.05). The mass of PTH secreted per burst was significantly reduced in all three groups; however, this was more pronounced in healthy controls compared with the two patient groups (Figure 3). Consequently, the pulsatile PTH secretion component was 51 ± 14% lower in PTX patients, 43 ± 18% lower in non-PTX patients, and 60 ± 25% lower in healthy controls. The foregoing alterations were accompanied by a similar decline in tonic secretion of 55 ± 25% in PTX-patients, 62 ± 5% in non-PTX patients, and 72 ± 4% in healthy controls. Approximate entropy remained unaltered during hypercalcemia in all groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study establishes the dynamics of PTH secretion after total PTX and heterotopic autotransplantation of parathyroid tissue. The physiologic, pulsatile mode of PTH release is profoundly disturbed during the first 2 mo after surgery, but it recovers partially in the long term. The deficient capacity to adapt to changes in plasma Ca2+ persists after autotransplantation.

By sonographic examination, no orthotopic parathyroid tissue persisted in situ, albeit observed in up to 1% of patients undergoing total PTX (23). Hence, the observed PTH secretion patterns originated from the transplanted parathyroid tissue with, at least initially, disrupted autonomic nerve supply. Remarkably, a few significant episodic pulsations of the hormone were detected even within the first 2 mo after surgery in each patient, although the degree of orderliness of PTH oscillations was reduced, and burst mass was blunted in three of the four patients. In patients studied at least 15 mo after surgery, the frequency of plasma PTH oscillations was normal, and the regularity of the pulsatile signals was greater. Assuming that autonomic neuronal input is responsible for the oscillatory organization of PTH secretion, the present findings are compatible with gradual reinnervation of the autotransplanted parathyroid tissue. Reinnervation has been demonstrated in various transplanted organs and tissues, such as heart, kidney, lung, pancreatic islet, adrenal gland, and also parathyroid gland (13,24–30). The rate and degree of reinnervation appear to vary among species and host tissues. In rat parathyroids autotransplanted under the renal capsule, ingrowth of sympathetic and parasympathetic fibers started as early as 3 wk post-surgery (13). Reinnervation began along incursive blood vessels and extended into the endocrine cell parenchyma after 20 wk. A bifunctional receptor molecule, neuropilin, is demonstratable in neurons, where it is involved in axonal guidance, and endothelial cells, where it supports neoangiogenesis (31,32). Thus reinnervation of transplanted organs may accompany revascularization under drive by this or related molecules.

Whereas reinnervation of transplanted tissues is a widespread phenomenon, the functional significance of this process is more controversial. In kidney allografts, neural regulation of hemodynamic processes is apparently not restored although nerve fibers extend along the arterial branches to the level of the interlobular arteries (33,34). In contrast, functional sympathetic reinnervation is evident in the transplanted human heart and rat adrenal gland (25–27). Porksen et al. (35) demonstrated coordinate pulsatile insulin secretion by isolated livers of diabetic rats given dispersed pancreatic islet grafts via intraportal infusion (35). Pulsatile insulin delivery was absent 2, 7, and 30 d after grafting, but recovered in all 12 animals examined after 200 d. At that time, nerve endings were detected in transplanted islets. These observations suggest but do not prove that autonomic reinnervation contributes to eventual coordinate pulsatile secretion by transplanted endocrine tissue. We speculated that intrahepatic ganglia might serve as pacemakers synchronizing oscillatory insulin secretion in this model. Such observations, in conjunction with rapid reinnervation of autotransplanted parathyroids in the rat model (13), support the concept that restitution of an autonomic neuroendocrine network may mediate gradual re-expression of pulsatile PTH secretion observed here.

Although spontaneous oscillatory PTH secretion was restored late after heterotopic autotransplantation, the capacity to modulate pulsatile PTH release in response to changes in plasma Ca2+ remained markedly diminished. The hypocalcemic response was especially blunted when compared with that in patients with secondary hyperparathyroidism without PTX. Notably, marked Ca2+ resistance in PTX patients emerged in the face of identical calcium kinetics; i.e., under equivalent regulatory stimuli imposed by the citrate and calcium clamp. We previously demonstrated that the sensitivity of oscillatory PTH secretion to changes in Ca2+ is inversely related to the degree of CRF and secondary hyperparathyroidism (4). An indication for PTX is usually severe hyperparathyroidism in the presence of hypercalcemia due to the presence of Ca2+- and vitamin D-resistant, autonomous, adenomatous tissue. On the molecular level, Ca2+ resistance in secondary hyperparathyroidism is associated with deficient expression of the calcium-sensing receptor (36). The latter defect should be most severe in patients requiring PTX. Although macroscopically less abnormal parathyroid tissue is selected for autotransplantation, persistent Ca2+ resistance suggests that the grafted tissues retained adenoma characteristics. It is of note that the Ca2+ insensitivity was observed in the presence of largely normalized serum PTH, Ca2+, phosphate, and alkaline phosphatase concentrations. These results are in keeping with a case study assessing the Ca2+ sensitivity of autotransplanted parathyroid tissue, which was marked by a rightward shift of the calcium setpoint and incomplete suppressibility of PTH secretion 15 d after PTX (37). Since autonomic innervation also affects the Ca2+ sensitivity of parathyroid tissue (9,38), denervation might influence early abnormalities. However, persistent Ca2+ hyporesponsiveness despite restoration of oscillatory PTH secretion patterns observed here in patients late after PTX suggest that functional reinnervation may not correct abnormal Ca2+ sensing. Thus the latter appears to be an intrinsic property of the autotransplanted, presumably adenomatous tissue.

In summary, restitution of oscillatory PTH secretion patterns after total PTX with heterotopic autotransplantation provides circumstantial evidence of autonomic reinnervation of parathyroid tissue. However, the release of high-frequency, high-amplitude PTH pulses under acute hypocalcemia, and hypercalcemia-induced silencing of PTH pulses are diminished even 1 to 3 yr post-PTX. Both findings denote persistence of calcium resistance in PTH autografts.


   Acknowledgments
 
The study was supported by Forschungsförderungsmittel des Rehabilitationszentrum für chronisch Nierenkranke, Heidelberg, and by General Clinical Research Center Grant #RR00585 to the Mayo Clinic and Foundation from the National Center for Research Resources (Bethesda, MD). The authors are grateful to Olaf Hergesell, Vedat Schwenger and Ms. Ingrid Zahnt for the active contribution to the study.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication August 28, 2002. Accepted for publication October 8, 2002.




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