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Nephrol Dial Transplant (2002) 17: 625-629
© 2002 European Renal Association-European Dialysis and Transplant Association

Total parathyroidectomy with autotransplantation in renal hyperparathyroidism: low recurrence after intra-operative tissue selection

Ulrich Neyer1,, Helmut Hoerandner3, Anton Haid2, Gerhard Zimmermann2 and Bruno Niederle4

1 Department of Nephrology and Dialysis, 2 Department of General Surgery, Landeskrankenhaus Feldkirch and 3 Elektronenmikroskopisches Labor Mauer, Vienna, Austria and 4 Department of Surgery, Division of General Surgery, Section of Endocrine Surgery, University of Vienna, Austria



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Total parathyroidectomy with simultaneous autotransplantation (AT) is a well-established surgical modality in the treatment of severe drug-resistant renal hyperparathyroidism. In literature, the high rate of graft-dependent recurrence seems a serious disadvantage. This complication can possibly be avoided by parathyroid tissue selection prior to AT.

Methods. Total parathyroidectomy with simultaneous AT was performed in 37 patients on intermittent haemodialysis treatment. Parathyroid tissue with a low proliferative potential (‘A-regions’) was selected for AT intra-operatively with a stereomagnifier. The mean post-operative follow-up was 37±24 months.

Results. Plasma levels of intact parathyroid hormone decreased from 1211±541 to 69±32 pg/ml, calcium from 2.49±0.27 to 2.17±0.30 mmol/l, phosphorus from 2.28±0.63 to 2.11±0.69 mmol/l, and total alkaline phosphatases from 272±210 to 117±70 U/l. Graft-dependent recurrent hyperparathyroidism occurred in one patient after 32 months and was cured by the selective removal of five enlarged autografts.

Conclusions. Simply discriminating between diffuse and nodular hyperplastic parathyroid tissue appears to be inadequate. Intra-operative tissue selection with a stereomagnifier may facilitate the identification and AT of tissue with optimal functional characteristics and a low proliferative potential, thus minimizing the rate of recurrent hyperparathyroidism.

Keywords: apoptosis; autotransplantation; proliferation; renal hyperparathyroidism; tissue selection; total parathyroidectomy



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Severe renal hyperparathyroidism (RHPT), a common complication in chronic dialysis patients, leads to nodular transformation of the parathyroids in up to 75% of cases [1]. Poor efficacy of 1,25-dihydroxy-vitamin D3 therapy in progressive RHPT [2] and the slow process of apoptosis [3] argue in favour of parathyroidectomy (PTX) [4,5]. The optimal surgical procedure is still controversial [5].

Total PTX without autotransplantation (AT) [6,7] is associated with an inherent risk of hypoparathyroidism and ‘adynamic bone disease’ [8]. Subtotal PTX [9] or total PTX with simultaneous AT can be expected to yield much more favourable results. Some authors reported the outcome of these techniques to be equal [1], while others showed the long-term results of total PTX with AT to be superior [9]. Nevertheless, some groups reported high relapse rates even after AT of diffusely hyperplastic tissue [1,6,10].

Niederle et al. [11] showed that careful intra-operative tissue selection with a stereomagnifier was essential for keeping the recurrence rates low. Poor ability to suppress and a high proliferative potential were found to have distinct macroscopic correlates [12].

We present the results of 37 consecutive patients who underwent total PTX and macroscopic tissue selection prior to AT.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
Thirty-seven consecutive patients (20 women, 17 men) with RHPT on maintenance haemodialysis (HD) treatment three times a week for 4–5 h underwent PTX. Their mean age was 50.6±13.4 (range 22–74) years. They had been on HD for 34.6±22.8 (range 1–77) months. The causes underlying chronic renal failure included chronic glomerulonephritis in 12 patients, adult polycystic kidney disease in eight, chronic interstitial nephritis in seven, vascular nephropathy in six, Alport's syndrome in three, and diabetic nephropathy in one patient.

Patients were selected for PTX if they showed severe renal osteodystrophy and if they failed to respond to calcitriol bolus therapy because of hypercalcaemia >2.6 mmol/l, an excess of serum calciumxphosphorus product (>6.0 mmol/l) in the presence of unchanged, markedly elevated serum parathyroid hormone (PTH) levels.

After PTX, all patients continued HD as described above using a dialysate calcium concentration of 1.5 mmol/l and calcium-based phosphate binder therapy. All patients received calcitriol therapy 0.25–1.0 µg daily for up to 6 months post-operatively. The mean post-operative follow-up was 37±24 months.

Surgical strategy
During bilateral cervical exploration, four parathyroid glands were removed in 31 patients and five glands in six patients. The volume of the glands was 1.0±0.6 (range 0.067–2.2) cm3.

Transcervical thymectomy and extirpation of retrothyroidal and paraesophageal fatty tissue were added to remove aberrant parathyroid tissue.

Histological correlates of macroscopic regions
After removal of the glands, the cross-sections were classified macroscopically with a stereomagnifier (magnification 5–60x). In type 1 (diffuse enlargement) and type 2 (nodular enlargement) glands A-regions (containing visible stromal fat cells—see below) and B-regions (containing no fat cells—see below) were distinguishable (Fig. 1aGo and b). In type 2 glands A- and/or B-regions were found between confined nodules (C-regions) (Table 1Go).



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  		Fig. 1.  (a) Macrophotograph of a continuous transition from an A- to a B-region. The B-region contains a cluster of oxyphilic cells, about 1 mm in diameter (ox), recognizable by a different colour and texture (magnification 35:1). (b) Small, presumptively focal proliferation (B-region), about 0.4x0.6 mm in size characterized by its pale colour and the complete absence of stromal fat cells, surrounded by A-regions with abundant stromal fat cells (magnification 60:1).

 

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  		Table 1.  Proposed macroscopic classification of parathyroid tissue in secondary uraemic hyperparathyroidism

 

Protocol for intra-operative tissue selection
A-regions were favoured for AT because of the optimal in vitro suppression of PTH secretion by high calcium levels [11]. The selected tissue (A-regions) was obtained from diffusely enlarged (type 1) glands in 15 patients and from nodular (type 2) glands in 22 patients. In 15 of these cases this was not from the smallest gland. It was divided into 1x1x2 mm fragments. Twenty of these fragments were autotransplanted into the non-shunt-bearing forearm, 10–20 fragments of A-regions were cryopreserved in each patient for delayed AT in case of graft failure. B-regions with poor suppressibility, as shown by Niederle et al. [11], and also with a tendency to proliferate [13] were avoided for AT whenever possible. C-regions were never used for AT.

For histological analyses cryosections, paraffin sections, and semi-thin sections were prepared. In selected cases electron microscopy was performed. Selected paraffin sections were stained with the proliferation markers PCNA and MIB-1. Apoptotic cells were identified by electron microscopy and in semi-thin sections.

A-regions represent parathyroid tissue with normotrophic cells in a trabecular arrangement. A normal calcium set point implicates that these cells will be inactive under hyperparathyroid conditions [11,14,15]. We therefore identified these regions by the classical signs of suppression, i.e. by the presence of stromal fat cells macroscopically (Fig. 1aGo and b) and by the presence of intracellular lipid and glycogen microscopically (Fig. 2aGo and b).



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  		Fig. 2.  Cytologic details of A- and B-regions. (a) Transition from A- to B-regions consisting mainly of chief cells. The chief cells from A-region show morphologic signs of prolonged inactivity, i.e. accumulation of intracellular lipid droplets (L) and areas of densely packed glycogen (gl). Section 0.8 µm, methylene blue to methylene violet, 560:1. (b) High-power view of another transition from A- to B-regions. The chief cells of A-region show intracellular accumulation of lipids (L) and some areas of densely packed glycogen (gl). The chief cells of B-region are arranged in a follicular pattern with small lumina (1–2 µm, arrows). Section 0.75 µm, methylene blue to methylene violet, 1000:1. (c) Oxyphilic B-region with high mitotic count (1:800, arrowhead) and prevalence of apoptosis (arrows) constituting about 20% of this cell population. Section 0.5 µm, toluidine blue, 660:1.

 
B- and C-regions represent dysfunctional hyperplastic tissue [11]. The diffuse type was named B, the nodular type C. Identification of C-regions was easy to define, B-regions were identifiable by the absence of fat cells (Fig. 1aGo and bGo) and contained cells which showed signs of slight (Fig. 2aGo and bGo) or severe hypertrophy. Typical morphologic signs of an abnormal secretory pattern included follicle formation, increase in the number of mitochondria (Fig. 3aGo and eGo), and vacuolization of cytoplasm [14,15]. High proliferative activity was reflected by the frequent occurrence of mitoses (Figs 2cGo and 3aGo) accompanied by strong PCNA and MIB-1 staining. Apoptosis, a mandatory element of clonal proliferation, was detected based on pycnotic (Figs 2cGo and 3bGo) or fragmented nuclei (Fig. 3cGo and d), concurrent with cytoplasmic PCNA and MIB-1 staining.



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  		Fig. 3.  Cytologic details of B- and C-regions. (a) Mitosis and microfollicle formation (arrows) in a B-region. (b) Condensed chromatin is indicative of apoptosis (arrows); section 0.5 µm, toluidine blue, 2000:1. (c) Same region under the electron microsope; section 0.08 µm, 2500:1. (d) Early apoptosis to condensed chromatin, intact nuclear envelope and nucleoli, 8000:1. (e) ‘Normal’ and apoptotic cell from a C-region with abundant mitochondria; in the apoptotic cell (lower part) mitochondria are hypertrophic, chromatin is condensed, nuclear membrane and Golgi apparatus are still intact, 12000:1.

 

Biochemistry
Plasma calcium, phosphorus, and total alkaline phosphatases were determined with the Hitachi 717 autoanalyzer. Plasma levels of intact PTH were measured with a commercially available two-site immunoradiometric assay (IRMA, Nichols Institute Diagnostics, San Juan Capistrano, CA, USA).

Recurrence of RHPT was defined by an increase in plasma PTH level >200 pg/ml in the presence of a normal plasma calcium level.

Graft function was assessed by the PTH gradient in the cubital venous blood between the grafted arm and the non-grafted arm after blocking to mean arterial pressure [15]. All results are expressed as means±SD.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Within the follow-up period, 33 patients (89%) showed normal graft function. Laboratory data of the 33 euparathyroid patients are shown in Table 2Go. The PTH gradient in the cubital venous blood between the graft-bearing and non-graft-bearing arm was 8.1±6.3, reflecting normal graft function.


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  		Table 2.  Plasma biochemistry of the 33 patients before and after total parathyroidectomy and autotransplantation (PTX+AT)

 
Two patients showed persistent HPT due to a fifth gland not removed during the initial operation. After cervical re-operation and extirpation of one supernumerary fifth gland in each patient, normal parathyroid function was documented.

One patient who had received a subfascial autograft constantly showed plasma PTH levels <7 pg/ml as a sign of graft failure. Plasma PTH levels promptly returned to normal (58 pg/ml) after the AT of cryopreserved tissue (A-regions of the same gland) into the brachioradial muscle. During re-operation none of the originally transplanted tissue fragments were detected at the original implantation site, suggesting preparative reasons for the dysfunction.

One patient developed graft-dependent recurrent RHPT at 32 months, which was successfully treated by the removal of five enlarged fragments under local anaesthesia. Plasma PTH drecreased from 874 to 99 pg/ml and remained in the normal range 84 months after graft reduction. On histological re-examination of the donor gland some small proliferating regions below the macroscopic detection limit were found as possible sources of recurrence.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In our opinion total PTX and AT seems superior to other modalities in the surgical management of RHPT, because: (i) the hyperplastic tissue is completely excised from the neck and mediastinum; (ii) removal of the totality of glands minimizes the risk of seeding proliferating cells by cutting through clonal proliferating regions; (iii) the forearm represents a confined haemodynamic compartment which permits easy functional testing in vivo; and (iv) re-operation, if required, is much easier in the forearm than in the neck.

It is accepted that nodular parathyroid tissue should be avoided for AT because of its high risk of proliferation resulting in graft-dependent recurrence [1,10]. Nevertheless, recurrence rates up to 80% have been reported even after AT of diffusely hyperplastic parathyroid tissue [1,6,10]. This suggests that it is inadequate to simply discriminate macroscopically between diffuse and nodular hyperplastic parathyroid tissue.

With a stereomagnifier, ‘eufunctional’ A-regions can be distinguished intra-operatively from ‘dysfunctional’ B-regions. These B-regions with a high proliferative potential occur in diffusely enlarged parathyroid glands [17] and between nodules of nodular enlarged glands. B-regions present a high risk of recurrence because of their high mitotic index [17].

In our study, graft-dependent recurrence after AT of tissue selected with a stereomagnifier was observed in only one out of 37 patients. Compared with the literature [1,6,10] this rate is extremely low. In more than half of the patients, the best-suited tissue for autografting (A-regions) was found in nodular glands. In 40% of the patients the smallest gland was not the best one for grafting. This suggests that following standard recommendations to use the smallest gland [9], preferably of the diffuse type for AT, might lead to high recurrence rates.

An analysis of histological details reported in the literature on graft-dependent recurrence of RHPT [18,19] showed many similarities. Proliferating autografts and the original glands presented virtually the same histological appearance. Focal accumulation of mitoses, altered nuclear morphology and an elevated DNA content were present throughout [18–20]. B-regions, which looked completely homogeneous to the naked eye, revealed focal accumulation of mitoses paralleled by high PCNA and MIB-1 appearance [17]. The concomitant focal accumulation of apoptotic cells suggested that they were the morphologic equivalent of proliferating regions in the exponential phase [3]. Small proliferations (0.5–2 mm) may be the only morphologic alteration in otherwise normal-looking parathyroid glands [17].

These proliferations are invisible to the naked eye, but can be detected with a stereomagnifier down to a size of 0.5 mm in diameter.

The cells in these regions show a very uniform ultrastructure similar to that of larger nodules, suggesting a monoclonal origin. They appear to signal the point in the time course at which pure hypertrophy turns into hyperplastic enlargement [3].

In conclusion, our observations emphasize the need for a highly elective tissue selection for parathyroid autografting, down to a small scale to avoid graft-dependent recurrence. Interestingly, we found almost normal tissue even in the most severely altered nodular glands, which fared better after autografting than tissue from small and/or diffusely enlarged glands containing B-regions.



   Acknowledgments
 
We are indebted to Elisabeth Muerzl for performing PCNA and MIB-1 staining and to Otto Freistaetter for his technical assistance. The study was supported by a grant of the Province of Vorarlberg, Austria.



   Notes
 
Correspondence and offprint requests to: Ulrich Neyer, MD, Department of Nephrology and Dialysis, Landeskrankenhaus, A-6800 Feldkirch, Austria. Email: ulrich.neyer{at}vol.at Back



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Gagné ER, Ureña P, Leite-Silva S et al. Short- and long-term efficacy of total parathyroidectomy with immediate autografting compared with subtotal parathyroidectomy in hemodialysis patients. J Am Soc Nephrol1992; 3: 1008–1017[Abstract]
  2. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest1993; 92: 1436–1442
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Received for publication: 28. 3.01
Revision received 2.11.01.
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