PARATHYROIDECTOMY IN RENAL HYPERPARATHYROIDISM

Since the hypothesis of Massry and Goldstein¹ on the toxicity of hyperparathyroidism (HPT) for the uremic patient, it became clear that HPT not only affects the skeletal system but also other organs especially in combination with hyperphosphatemia^2-6. The impact on cardiovascular mortality in the prevalent⁷ and incident⁸ dialysis population makes prevention of HPT obligatory.

In chronic renal failure hypocalcemia, hyperphosphatemia and low 1,25 (OH)₂D₃ stimulate synthesis and secretion of parathyroid hormone (PTH) and cellular kinetics of the parathyroid gland. After initial hypertrophy diffuse polyclonal proliferation occurs. Later monoclonal proliferation starts in still diffuse enlarged glands. Enlargement of these focal proliferations leads to nodular glands. A multiclonal proliferation seems to be the rule since several nodules can be found usually in one gland⁹. This leads to an impaired sensitivity to conservative medical therapy due to a decreased density of Vitamin D receptors^{10, 11} and calcium-sensing-receptors^{12, 13}. In the advanced and severe stage of renal HPT all parathyroid glands are enlarged and almost all are nodular altered.

Surgical removal of the glands is necessary at the latest in this stage in order to control the deleterious effects of high PTH values^{14, 15, 16, 17}.

The percentage of dialysis patients in need of PTx increases continuously with duration of dialysis treatment. After 15 years of treatment 40% of all patients were parathyroidectomized according to the EDTA-report from 1991¹⁸. Interestingly, recent data showed that the number of PTx did not change significantly during a decade¹⁹ despite progression in medical therapy with phosphate binders and Vitamin D analogues. Newer calcimimetic agents, however, may prevent the development of HPT in future²⁰.

1. Plasma PTH-values > 700 pg/ml combined with hypercalcemia or hyperphosphatemia or calcium-phosphate-product > 5,5 mmol²/L².
2. Size of at least one parathyroid gland more than 0,5 cm³ in volume or 1,0 cm in diameter imagined by colour-doppler-ultrasonography.
3. Radiological or biochemical signs of osteoclastic bone resorption or clinical signs of HPT like pruritus, calciphylaxy, nontraumatic bone fractures or rupture of tendons.

In our experience high dose therapy with Vitamin D in this advanced stage is not effective to cure the HPT in patients persistently and may additionally cause soft tissue- and/or vascular calcifications.

With the exception of sonographic visualisation we consider preoperative localisation of the parathyroid glands not to be useful due to the low diagnostic sensibility of CT, MRI and scintigraphy.

Three main types of surgical procedures for PTx in patients with renal HPT are currently performed:

• subtotal parathyroidectomy
• total parathyroidectomy with autotransplantation (AT)
• total parathyroidectomy without autotransplantation

Irrespective of the method chosen, the most important factor for outcome is the experience of the endocrine surgeon. All four parathyroid glands should be dissected. Transcervical thymectomy and extirpation of retrothyroidal and paraesophageal fatty tissue should be performed to remove supernumerary parathyroid glands²¹. It is recommended to cryopreserve diffuse parathyroid tissue for eventual reimplantation in case of postoperative hypoparathyroidism^{22, 23}.

Subtotal PTx is probably the most often performed surgical procedure to date^24-28. After identifying all four parathyroid glands, the smallest and least nodular transformed gland is resected only partially. Approximately 100 mg of tissue is left in the neck visually ascertaining a satisfactory blood supply. The other three (or more) glands are excised totally. This procedure is associated with the risk of postoperative hypoparathyroidism^{26, 28} and therefore with the development of "low turnover bone disease"^{29, 30}. The more severe complication is the recurrence of HPT in 10-80 % of the patients^{26, 31, 32} which increases with time of follow-up. The recurrence of HPT under the persisting uremic condition is quite likely with the observation of monoclonal cells with a high proliferation rate not only in nodular^{9, 33} but also in diffuse hyperplastic parathyroid tissue³⁴. A further problem is the development of "parathyromatosis", an uncontrolled growth of clonal proliferating cells seeded in the neck by cutting through the gland^{35, 36, 37}. A new technique using fibrin adhesive for sealing the cutting area of the gland might be an interesting alternative to prevent seeding of parathyroid cells³⁸.

In case of recurrence of HPT, a successful reoperation of the neck is difficult or even impossible in several cases^39-41.

In our opinion subtotal-PTx has serious disadvantages as described above and is therefore not the method of choice in our clinic.

Total PTx was first described by Felts et al⁴² and Ogg⁴³. The advantage of minimizing the risk of recurrence of HPT^44-51 is in opposition to the disadvantage of absent PTH on bone turnover^{29, 30}. Despite lack of evidence of clinical skeletal problems^44-51, histological examination of bone biopsies in these patients showed "low turnover bone disease"^{44, 51}. This may cause severe bone problems especially after subsequent kidney transplantation. It is therefore advisable, to reserve total PTx without AT only to patients not registered on a waiting list for kidney transplantation.

Many authors described measurable or even elevated PTH plasma values in the long term follow-up after total PTx^44-52. These may have been caused by remaining parathyroid cell nests in the neck and therefore PTx can not be considered to be total.

If PTx is really complete, delayed autotransplantation of cryopreserved parathyroid tissue with low proliferation potential may become important in the future⁵³.

Autotransplantation of tissue from the smallest and least nodular appearing gland is performed immediately after total PTx. 20 - 25 tissue fragments sized 1x1x2mm are implanted in 4 - 5 compartments of the musculature of the non-shunt bearing forearm^{54, 55}. It is useful to monitor intraoperatively the PTH plasma values. If after excision of the 4^th gland PTH does not fall below 30 % of the preoperative value, extensive search for a supernumerary gland is indicated⁵⁶.

Postoperative hypoparathyroidism is extremely rare and can be cured by reimplantation of cryopreserved tissue²³.

Graft dependent recurrence of HPT was reported in 10-80 % of patients, with increasing frequency with time on dialysis treatment.^{31, 32, 46, 57-61}. This shows that the standard recommendation to use diffuse hyperplastic parathyroid tissue for autografting is insufficient. Small clonal proliferating regions situated in diffusely enlarged glands may cause severe recurrences^{32, 62-71}. Histological details from the literature dealing with recurrence of HPT show many similarities: virtually the same histological pictures were presented from proliferating autografts as well as from original glands. In all cases focal accumulation of mitoses, altered nuclear morphology and elevated DNA content have been found^{53, 63, 71}.

Only with a stereomagnifier it is possible to distinguish intraoperatively eufunctional A-regions from dysfunctional B-regions in purely diffuse hyperplastic areas of parathyroid glands^{72, 73}.

A-regions represent parathyroid tissue with normal function, proven by their optimal in-vitro suppressibility of PTH-secretion by high calcium⁷³. A-regions can be recognized macroscopically by the occurrence of stromal fat-cells and microscopically by presence of intracellular lipid and glycogen. These regions show a low mitotic index and a low proliferation activity by immunohistochemical staining. Tissue from A-regions is recommended for autotransplantation⁷⁴.

B-regions can be identified macroscopically by the absence of fat cells. Microscopically cells of these regions show signs of slight or severe hypertrophy and almost complete absence of intracellular lipid and glycogen. Morphological signs of secretory disturbance are follicle formation, increase in the number of mitochondria and vacuolisation of cytoplasm. Proliferative activity is reflected by frequent occurrence of mitoses accompanied by strong PCNA and MIB-1 staining. The cells in these regions show a very uniform ultrastructure, similar to larger nodules, suggesting monoclonal expansion. This seems to represent the time of switchover from pure hypertrophy to hyperplastic enlargement⁷⁵. Medium sized B-regions show poor suppressibility⁷³ and high proliferation rate^68,71. They should never be used for AT^{53, 69, 74}.

Following these recommendations of intraoperative tissue selection for immediate autografting Niederle at al⁷⁴ and we^{76, 77} could obtain a very low graft dependent recurrence rate of HPT in uremic patients after total PTx. Delayed AT of cryopreserved tissue after staining of tissue samples with proliferation markers is an alternative option⁵³.

Persistence of HPT after PTx can be caused by a supernumerary gland or residual parathyroid tissue left in the neck after subtotal PTx. Recurrence is observed by definition 6 months or later after PTx. The site of recurrence after PTx + AT can be diagnosed by functional^78-81 and imaging^{82, 83} tests.

HPT persists in many cases after successful kidney transplantation in correlation to the extent of pretransplant HPT⁸⁴, possibly because of the slow process of apoptosis^85-87. If hypercalcemia occurs PTx is necessary⁸⁵. In this situation we prefer total PTx with AT to prevent hypoparathyroidism postoperatively on the one hand and recurrence of HPT on the other hand, if kidney graft function is worsening with time.

We consider total parathyroidectomy and autotransplantation to be the superior method for surgical treatment of advanced renal HPT because:

1. The hyperplastic tissue usually gets excised completely from the neck region.
2. Removal of the glands in toto minimizes the risk of seeding proliferating cells by cutting through clonal proliferating regions.
3. The tissue may be accurately analyzed on cross sections before autografting and tissue with normal function can be selected.
4. PTH plasma values can be maintained in the normal range postoperatively and therefore a sufficient bone turnover is achievable even after kidney transplantation.
5. The forearm represents a confined hemodynamic compartment which allows easy functional testing in vivo.
6. Reoperation, if required, is much more easily performed on the forearm in local anesthesia than on the neck.

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