Parathyroidectomy in dialysis patients

Kidney International, Vol. 61, Supplement 80 (2002), pp. S161–S166

Parathyroidectomy in dialysis patients ANGEL L.M. DE FRANCISCO, GEMA FERNA´NDEZ FRESNEDO, EMILIO RODRIGO, CELESTINO PIN˜ERA, J.A. AMADO, and M. ARIAS Servicio de Nefrologı´a y Endocrinologı´a, Hospital U Valdecilla, Universidad de Cantabria, Santander, Spain

Parathyroidectomy in dialysis patients. Subtotal parathyroidectomy or total parathyroidectomy (PTx) with autotransplantation are surgical procedures considered while the patient is included on the waiting list for renal transplantation. Total PTx alone is based in the posibility that a fragment of tissue (nodular hyperplasia in particular) left in the same pathophysiological environment of long term dialysis would show the same behavior and reproduce in time the same clinicopathological picture. The persistence of uremia induces a continued growth stimulus developping residual hyperplasia and consequently a very high risk of recurrence. We performed total PTx alone in 15 uremic patients excluded for renal transplantation 10 patients with undetectable iPTH serum concentration and were followed up for 37 to 144 months. There was no evidence of clinical bone disease (bone pain or fractures). Bone mineral lumbar spine and hip density was measured at the end of follow-up. The z score data showed that all patients had a bone mass similar than that expected for their age. Bone biopsies performed in four patients showed a uniform picture of low turnover without aluminium staining. Calcification of small arteries (digital and arcade vessels in hands and feet) were evaluated pre and post total PTx alone in nine out of the 10 patients with undetectable PTH levels.The small vessel calcification was present in five patients at the moment of PTx. At the end of the long term follow-up only one patient showed progression. In conclusion, total PTx without autotransplantation is a very effective and adecuate treatment for refractory severe hyperparathyroidism in patients excluded for renal transplantation. Aluminium related osteopathy post PTx is a risk to be controlled with aluminium “free” dialysis water and avoiding aluminium containing phosphate binders.

Although the majority of patients with secondary hyperparathyroidism caused by chronic renal failure are successfully managed medically, in a considerable number of patients with refractory symptoms, palliative surgical treatment is necessary. PREVALENCE AND RISK FACTORS In spite of the introduction of new therapeutical approaches, such as new phosphate binders, vitamin D Key words: chronic dialysis, parathyroidectomy, parathyroid hyperplasia.

 2002 by the International Society of Nephrology

metabolites, or intravenous calcitriol, the mean annual incidence of parathyroidectomy (PTx) among all renal replacement therapy (RRT) patients included in the European Dialysis and Transplantation Registry was similar in the periods 1983 to 1985 and 1986 to 1988 [1]. More recent reports showed that the incidence of PTx in patients who started RRT between 1990 and 1992 was no different from that observed in patients who started RRT between 1983 and 1985 [2]. The prevalence of PTx in almost 14,180 patients included in the Lombardy Registry who received RRT between 1983 and 1996 was 9.2% after 10 to 15 years, and increased with the duration of RRT to 20.8% after 16 to 20 years This figure is even higher in other reports with 40% after 15–20 years of treatment [3]. Prolongation of uremic state explains this high prevalence of parathyroidectomy in this group of patients. The relative risk factors for PTx were significantly higher in women and lower in elderly and diabetic patients. The relative risk for PTx (adjusted for gender, age, and nephropathy) was higher in the patients on peritoneal dialysis than in those on hemodialysis and decreased after transplantation [2]. PARATHYROID HYPERPLASIA RESISTENT TO CALCITRIOL One of the characteristic features of very severe secondary hyperparathyroidism in uremic patients is parathyroid hyperplasia. There are two types of parathyroid hyperplasia: diffuse hyperplasia and nodular hyperplasia. The latter exhibits at least one well circumscribed encapsulated nodule and each nodule usually consists of a single cell type with fat-free accumulation. As the gland becomes heavier the hyperplastic pattern changes from initial diffuse hyperplasia to nodular hyperplasia, and ultimately to a single nodule. Nodular hyperplasia is the more advanced type of hyperplasia and is seen more often in large glands where monoclonal proliferation may be present irrespective of the size of the nodule [4]. Cells in nodular hyperplasia have a significantly lower density of vitamin D receptors [5] and lower calcium

S-161

S-162

de Francisco et al: Parathyroidectomy in dialysis patients

sensor receptors [6] than those in diffuse hyperplasia. These findings can explain the resistance of parathyroid cells in parathyroid glands with nodular hyperplasia to calcitriol therapy. This is a very important point in terms of clinical management of secondary hyperparathyroidism since more than 85% of the parathyroid glands weighing more than 500 mg exhibit nodular hyperplasia [7] and patients with at least one gland larger than 0.5 cm3 or 1 cm in diameter are usually refractory to calcitriol pulse therapy in the long term [8]. It is also important to consider that, with time on dialysis, the size of the parathyroids increases and an ever higher proportion of patients also show nodular rather than diffuse hyperplasia [9]. Arnold et al examined hyperplastic glands with secondary hyperparathyroidism and 75% of the glands revealed monoclonal growth [10]. Therefore, nodular hyperplasia is the commonest histological finding in secondary hyperparathyroidism. Forty three out of 60 patients (72%) in our series of parathyroidectomies in chronic renal failure patients showed nodular hyperplasia [11]. INDICATIONS FOR PARATHYROIDECTOMY Parathyroid gland size and PTH levels 8–20-fold above the normal range are critical for long term prognosis of calcitriol pulse therapy in chronic dialysis patients (abstract; Kitaoka et al, J Am Soc Nephrol 2:637A, 1991) and severe nodular parathyroid hyperplasia is found in many such patients. Ritz et al proposed that parathyroidectomy should be seriously considered when the parathyroid mass, as estimated by imaging procedures exceeds approximately 1 cm3 or 1 gr [13]. Clasical indications for parathyroidectomy are severe hyperparathyroidism (PTH ⬎1000 pg/mL) resistant to medical therapy in the presence of: hypercalcemia, bone pain, and severe hyperparathyroid bone disease, metastasic calcifications, intractable pruritus, or otherwise unexplained symptomatic myopathy. Enlarged parathyroid glands detected by ultrasound (glandular weight over 500 mg) are very frequently nodular hyperplastic glands and hyperparathyroidism may be refractory to medical treatment TREATMENT OF REFRACTORY HYPERPARATHYROIDISM Ethanol injection Selective percutaneous ethanol injection into the largest glands until PTH levels falls to less than 200 pg/mL has been advocated [14]. In a survey in 46 patients resistant to calcitriol pulse therapy all glands larger than 5 mm in diameter were destroyed by ethanol guided by power Doppler flow mapping. Serum iPTH levels decreased from 633 ⫾ 359 to 289 ⫾ 222 after one year [15]. However

there is a high degree of operator dependence, and because the risk of complications such as laryngeal palsy, the difficulty of a surgical exploration following failed ethanol ablation, and the limited experience, the technique is regarded as experimental alternative to parathyroidectomy. Surgical parathyroidectomy Three main types of surgical approaches have been advocated for PTx: subtotal parathyroidectomy, total parathyroidectomy with parathyroid autotransplantation, and total parathyroidectomy without autografting. Subtotal parathyroidectomy, and total parathyroidectomy with parathyroid autotransplantation. Many authors recommend subtotal PTx or total PTx with autotransplantation although both procedures carry some disadvantages, including the risks of permanent hypoparathyroidism and recurrence of bone disease [16–17]. Results obtained with subtotal PTx are very similar to total PTx with autotransplantation [18] and recurrent or persistent hyperparathyroidism is presented in 5–15% of cases. However, most published series have a mean follow up period of less than 3 years and some series do not distinguish between patients remaining on dialysis and those who have been transplanted. Renal failure is a powerful stimulus for parathyroid cell proliferation, and if there is any residual parathyroid tissue after parathyroid surgery and the patient remains on dialysis for several years, then the autonomus hyperparathyroidism is likely to recur. Gagne´ et al [19] observed that among the twelve patients with a time period of more than 90 months after subtotal parathyroid surgery, eight had recurrence of severe hyperparathyroidism with intact PTH levels ⬎500 pg/mL. Higgins et al [20] also showed a high recurrence of hyperparathyroidism more than 5 years after total parathyroidectomy with an autograft with only 20% of patients remaining on dialysis having normal PTH concentrations. Tominaga et al [21] have recently published the results of 1053 patients on dialysis who underwent total parathyroidectomies with forearm autograft. In order to avoid the remaining supernumerary glands they routinely performed excision of the fat tissue sorrounding the parathyroid glands, bilateral removal of the thymic tongue, and bilateral opening of the carotid sheats. They selected diffuse type hyperplasic tissue for grafting or, if impossible, fragments from the smallest gland. In spite of this excellent surgical strategy, persistent hyperparathyroidism was diagnosed in 4% of the patients and the incidence of recurrent hyperparathyroidism was 10% in the third year, 20% in the fifth year, and 30% in the seven years after parathyroidectomy. When nodular hyperplasic glands were autografted, the incidence of recurrence was significantly higher than when diffuse

de Francisco et al: Parathyroidectomy in dialysis patients

hyperplasia was transplanted (60% and 20% at 10 years for nodular and diffuse, respectively). Therefore, there is a high incidence of recurrent hyperparathyroidism in patients who remain on long term dialysis. But in some series, subtotal parathyroidectomy or total parathyroidectomy with autograft are frequently followed by hypoparathyroidism. Gagne´ et al [19] in a retrospective study performed in chronic hemodialysis concluded that, although excellent short term results were obtained with both procedures, satisfactory long term control of parathyroid gland function was achieved in only one third of the patients, the other two thirds remaining either hypoparathyroidic or developing recurrent hyperparathyroidism, and recurrence of hyperparathyroidism was more frequent with nodular autografting The problem of origin of oversecretion of PTH after total parathyroidectomy with forearm implant. Reoperations in the cervical region are associated with high complication rates and implantation of parathyroid tissue in the forearm was developed to allow, if necessary, removal of parathyroid tissue. However there have been reports of patients in whom the implanted tissue continued to grow with alarming rapidity [22–24]. Transplanted parathyroid fragments derived from glands weighing more than 0.5 g, and consequently showing nodular hyperplasia, relapse frequently [7]. Resection of the grafted tissue usually removes all palpable parathyroid nodules and is not always followed by a reduction in the PTH secretion, since parathyroid tissue has ability to migrate away from the implantation [25]. Usually it is not difficult to diagnose graft dependent recurrent HPT based on PTH gradient and image techniques. However sometimes it is difficult to localize the source of hormone excess, i.e., autografted parathyroid tissue, residual parathyroid glands in neck or mediastinum, implantation of parathyroid tissue in surrounding tissue, or metastasis of parathyroid carcinoma. We have developed a technique for localizing the origin. It involves total ischemic blockade of the graft bearing arm using tourniquet and measurement of circulating iPTH levels. If the serum level of circulating iPTH rapidly decreases during blockade of graft bearing arm (PTH mean life 2 min), this suggests that the origin of excess PTH secretion is the autograft whereas when the iPTH level does not change during blockade the origin is possibly parathyroid tissue located in the neck or mediastinum [26]. Total PTx without autografting. Total PTx is based in the possibility that a fragment of tissue (nodular hyperplasia in particular) left in the same pathophysiological environment of long term dialysis would show the same behavior and reproduce in time the same clinicopathological picture. However, total PTx may not be total. Detectable parathyroid hormones have been reported even after total PTx in many patients [27], probably due either to fragments of parathyroid tissue left in place

S-163

after gland biopsies or to additional sites of parathyroid tissue. Ljutic et al [28] reported 27 patients who underwent total PTx with four or more glands removed and immunologically detectable PTH persisting in 23, and concluded that PTx was incomplete in the majority of patients. Stracke et al reported a high percentage of patients with detectable PTH: considering only those patients in which four or more parathyroid glands were removed, PTH levels were less than normal in three patients, normal in five patients, and increased in seven patients at follow-up [29] The persistence of uremia induces a continued growth stimulus developing residual hyperplasia. The main drawback of total PTx alone is the increased risk of adynamic bone disease and, for some authors, the possibility of vascular calcifications. LONG TERM SUCCESSFUL TOTAL PARATHYROIDECTOMY WITHOUT AUTOGRAFTING IN SANTANDER Ten patients under hemodialysis therapy at Valdecilla Universitary Hospital (Santander) were treated with total parathyroidectomy for uncontrolled secondary hyperparathyroidism in the time period between 1989 and 1999. The patients were selected among 15 patients treated with four glands parathyroid extirpation due to very low or undetectable parathyroid hormone levels for more than two years after surgery. All were excluded for renal transplantation. Age, gender, renal disease, age at PTx, time on dialysis before and after total PTx, gland histology, PTH at surgery and at the end of follow-up, are shown in Table 1. Nine patients were on hemodialysis 4 h three times a week, and one patient was under CAPD. The indication of PTX was made because of vitamin D resistent severe clinical, biochemical, and radiological hyperparathyroidism with confirmed histological osteitis fibrosa aluminium negative in four cases. All patients had an increase in PTH above ten times the normal range with normal or elevated serum calcium. Total parathyroidectomy was performed in the standard manner and all removed material was histologically examined. One half of each parathyroid gland was maintained by criopreservation in each case. During the postoperative period patients were treated with supplemental calcium and calcitriol in order to maintain normal serum calcium levels. Patients were followed-up 37 to 144 months. Studies were performed at the end of follow-up post total PTx calcium, phosphate, and bone serum markers such as osteocalcine, bone phosphatase alkaline, carboxiterminal cross-linked telopeptide type I collagen, and carboxyterminal propeptide of type I procollagen and bone biopsy (obtained in four patients) are shown in

S-164

de Francisco et al: Parathyroidectomy in dialysis patients Table 1. Details of patients who underwent total parathryoidectomy (PTx) without autografting On dialysis

Patient

Gender

Renal disease

Age at PTx

DFL TGR CAO CFF HAM PPR LTC NGS SCR PLC

F F F M M M F M F F

Interstitial Interstitial Congenital Glomerular Interstitial Vascular Glomerular Vascular Unknown Interstitial

63 68 35 62 72 50 47 53 35 50

After PTx

Months 128 250 120 140 80 120 14 17 204 60

144 76 72 72 56 50 48 41 39 37

PTH level Pre

Post

Histology

650 1000 2308 940 1374 1150 2206 2082 1100 1541

⬍5 ⬍5 ⬍5 6 ⬍5 ⬍5 ⬍5 ⬍5 ⬍5 ⬍5

HD HN HN HD HN HN HN HN HD HN

Normal range of IPTH is 10 to 60 pg/mL. Abbreviations are: HD, diffuse hyperplasia; HN, nodular hyperplasia; F, female; M, male.

Table 2. Follow up of serum bone markers after total PTx without autotransplantation Patient

Months after PTX

Calcium (8.5–10 mg/dL)

Phosphate (3.0–5.0 mg/dL)

BAP (10–22 UL)

Osteocalcine (10–40 ng/mL)

Telopeptide (1.8–5 ng/mL)

Propeptide (69–163 ng/mL)

DFL TGR CAO CFF HAM PPR LTC NGS SCR PLC

144 76 72 72 56 50 48 41 39 37

8.8 9.2 8.3 10.1 9.8 9.6 9.1 8.9 10.2 9.5

5.3 6.1 4.2 3.9 6.3 5.8 4.9 3.3 4.5 6.8

9.1 13.5 14.5 13 12.8 21.2 13.9 19 10.1 14.2

70 86 60 68 61 24 31 24 61 109

37 38 23 28 27 43 22 34 33 96

97 76 183 67 106 184 178 74 104 140

Bone biopsy ABD Al ABD Al — — ABD Al ABD Al — — — —

neg neg neg neg

ABD is adynamic bone disease.

Table 3. Bone mineral density in patients at the end of follow-up L1–L4 Patient BMD g/cm2 DFL TGR CAO CFF HAM PPR LTC NGS SCR PLC

1.001 0.629 1.153 0.962 1.297 0.858 1.358 0.975 1.390 0.928

T ⫺0.42 ⫺3.80 ⫹0.97 ⫺1.17 ⫹1.87 ⫺2.12 ⫹2.83 ⫺1.05 ⫹3.12 ⫺1.08

Femoral neck Z score BMD g/cm2 ⫹1.20 ⫺1.80 ⫹1.02 ⫺0.52 ⫹2.81 ⫺1.78 ⫹3.33 ⫺0.63 ⫹3.21 ⫺0.32

0.649 0.596 0.905 0.748 0.721 0.788 1.021 0.768 0.833 0.864

T

Z score

⫺2.45 ⫺2.98 ⫹0.10 ⫺2.10 ⫺2.34 ⫺1.81 ⫹1.26 ⫺1.99 ⫺0.62 ⫺0.30

⫺0.64 ⫺0.80 ⫹0.34 ⫺0.51 ⫺0.03 ⫺0.65 ⫹2.01 ⫺0.72 ⫺0.33 ⫹0.70

Table 2. Bone mineral density measurements for lumbar spine and hip (dual X ray absorptiometry) are shown in Table 3. Skeletal surveys at surgery and at the end of the study were compared by two of the authors. Peripheral vascular calcifications were studied with X ray films of hands and feet Bone mineral density At the end of follow-ups after total PTx only one out of the 10 patients had BMD in the range of osteoporosis at L1-L4 and at femoral neck sites (more than 2.5 SD below the mean of peak bone mass (T ⬍ ⫺2.5). Osteope-

nia was present in four patients in L1-L4 and in five patients at femoral neck (more than 1 SD below the mean of peak bone mass (T ⬍ ⫺1). Z score data showed that all patients had a bone mass similar than that expected for their age [30]. Similar results in BMD were obtained by Kaye et al [27] in a long term follow up study (mean 3.8 years) following elective total parathyroidectomy in 13 patients. They observed increments in bone mineral density in all patients except two which showed a small decline. At the same time, bone histomorphometry in six patients a median of 1.5 years following PTX showed a uniform picture of low turnover. Other studies have also shown an increase in BMD after successful parathyroidectomy, with better recovery in patients with osteoporosis [31]. Increments in bone mineral density are explained by a higher depression in resorption than in formation. Bone biopsy: Adinamic bone disease Four patients who underwent bone biopsy 50, 56, 76, and 144 months after total PTx showed adynamic bone disease with low bone turnover aluminium negative characterized by low bone resorption and formation with normal or low osteoid tissue. There is a legitimate concern that the complete or near complete removal of parathyroid hormone may have deleterious consequences

de Francisco et al: Parathyroidectomy in dialysis patients

for the skeleton. Unfortunately we could not study all patients with bone histology, but this histological picture is universally associated with low levels of PTH, and most dialysis patients with a PTH ⬍100 ng/L will have adinamic bone disease [32]. The changes in biochemical bone markers correspond to histological findings with an important reduction in resorptive activity. Low bone remodelling lesions are quite frequent accounting in some series for almost one half the lesions observed in patients under dialysis treatment [33–34]. Years ago this condition was ascribed to aluminium bone intoxication [35], a form of the disease associated with substancial morbidity in the form of bone pain and increased fracture incidence [37]. Nowadays most cases are clearly unrelated to aluminium [33], a form generally asymptomatic, and the majority of patients with low bone remodelling we see now are free of symptoms, and many of them should not be considered as having disease. Most of the evidence in patients with low bone remodelling indicates that the incidence of bone pain, hypercalcemia, and bone fractures is related to the presence of more than 20% of bone surface covered by aluminium [33, 37]. An association of total PTx with adverse long-time effects on bone in the absence of aluminium bone disease has not been described in the literature. No clinical bone disease associated with low PTH was observed in our patients. Carpal tunnel syndrome and/or shoulder pain in two patients under dialysis for six and eleven years were related to ␤2 amyloidosis. Radiology: Fractures and vascular calcifications Although lower PTH less than 195 pg/mL has been related to an increase in the risk of having a hip fracture [38], and a reduced bone turnover will reduce the capacity of bone to repair microfractures resulting in an increase fracture risk independent of bone mass [38–40], radiological fractures were not detected in any patient in this study. Calcification of small arteries (digital and arcade vessels in hands and feet) were evaluated pre and post total parathyroidectomy in nine out of the 10 patients with undetectable PTH levels.The small vessel calcification was present in five patients. At the end of the followup only one patient showed progression. In a previous study in 1985 we observed that small peripheral arterial calcification developed or progressed in 56% of the patients after successful parathyroidectomy [11]. The high incidence of aluminum detected in bone biopsies and differences in vitamin D and calcium products indicated at that time to control calcium balance could explain these differences. Patients with adynamic bone have abnormal calcium homeostasis with an increased risk of extraosseous calcifications [41]. Hyperparathyroidism, high calcium/phosphate product, vitamin D analogs, advanced glycation end

S-165

products (AGEs), warfarin and possibly other poorly defined elements of the uremic milieu may all contribute to vascular calcification [42]. The extent of arterial calcification increases also with age and the duration of dialysis [43]. Patients with adynamic bone disease are more susceptible to develop iatrogenic hypercalcemia which may result in arterial calcifications caused by the use of calcium and lower metabolic activity. Among our patients with total absence of PTH, progression of small vessel calcification was not particularly observed. Nevertheless, more sensitive methods (helical or electron-beam computed tomography) should be used to assess vascular calcifications. Since aortic stiffness and calcification are related to cumulative amount of calcium-containing phosphate binders consumed, it is prudent to aim for a rigorous control of calcium phosphate based in non calcium containing phosphate binders in uremic patients and particularly in hypoparathyroid dialysis patients [44]. CONCLUSION Which is the best surgical procedure to the management of vitamin D resistant severe secondary hyperparathyroidism in dialysis patients? We believe that for patients not included in the waiting list for renal transplantation, total parathyroidectomy alone should considered. One important advantage is the absence of recurrence. Long term follow-up of 10 hypoparathyroid patients with histologically proven adynamic bone disease aluminium negative revealed good clinical tolerance, bone mineral mass similar to that expected for their age, no evidence of fractures, and no significant progression in small vessel calcifications. Reprint requests to Dr. Angel L.M. de Francisco, Servicio de Nefrologı´a, Hospital U Valdecilla, Universidad De Cantabria, Santander, Spain. E-mail: [email protected]

REFERENCES 1. Fassbinder W, Brunner FP, Brynger H, et al: Combined report on regular dialysis and transplantation in Europe XX. Nephrol Dial Transplant 6(Suppl 1) S4–S65, 1991 2. Malberti F, Marcelli D, Conte F, et al: Parathyroidectomy in patients on renal replacement therapy: an epidemiologic study. J Am Soc Nephrol 12:1242–1248, 2001 3. Fournier A, Dru¨eke T, Morinie´re PH, et al: The new treatments of hyperparathyroidism secondary to renal insufficiency. Adv Nephrol Necker Hosp 21:237–306, 1992 4. Tominaga Y, Kohara S, Namii Y, et al: Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism. World J Surg 20:744–750, 1996 5. Fukuda N, Tanaka H, Tominaga Y, et al: Decreased 1.25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92:1436–1443, 1993 6. Gogusev J, Duchambon P, Hory B, et al: Kidney Int 51:328–336, 1997 7. Tominaga Y, Tanaka Y, Sato K, et al: Histopathology, pathophysiology and indications for surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 13:78–86, 1997

S-166

de Francisco et al: Parathyroidectomy in dialysis patients

8. Fukagawa M, Kitaoka M, Yi H, et al: Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long term prognosis of calcitriol pulse therapy in chronic dialysis patients. Nephron 68:221–228, 1994 9. Mendes V, Jorgetti V, Nemeth J, et al: Secondary hyperparathyroidism in chronic hemodialysis patients: a clinico-pathological study. Proc Euro Dial Assoc 20:731–738, 1983 10. Arnold A, Brown MF, Uren˜a P, et al: Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 95:2047–2053, 1995 11. De Francisco ALM, Ellis HA, Owen JP, et al: Parathyroidectomy in chronic renal failure. Quart J Med 55:289–315, 1985 12. Deleted in proof. 13. Ritz E: Which is the preferred treatment of advanced hyperparathyroidism in a renal patient: early parathyroidectomy should be considered as the first choice. Nephrol Dial Transplant 9:1816– 1821, 1994 14. Giangrande A, Castiglioni A, Solbiati L, Allaria P: Ultrasound-guided percutaneous fine-needle etanol injection into parathyroid glands in secondary hyperparathyroidism. Nephrol Dial Transplant 7:412–421, 1992 15. Kakuta T, Fukagawa M, Fujisaki T, et al: Prognosis of parathyroid function after successful percutaneous ethanol injection therapy guided by color Doppler flow mapping in chronic dialysis patients. Am J Kidney Dis 33:1091–1099, 1999 16. Llach F: Parathyroidectomy in chronic renal failure: Indications, surgical approach and the use of calcitriol. Kidney Int 38(Suppl 29):S62–S68, 1990 17. Dru¨eke TB, Zingraff J: The dilemma of parathyroidectomy in chronic renal failure. Curr Opin Nephrol Hypertens 3:386–395, 1994 18. Kaye M: Parathyroid surgery in renal failure: Semin Dial 3:86– 92, 1990 19. Gagne´ ER, Uren˜a 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 Nephrol 3:1008–1017, 1992 20. Higgings RM, Richardson AJ, Ratcliffe PJ, et al: Total parathyroidectomy alone or with autograft for renal hyperparathyroidism? Quart J Med 79:323–332, 1991 21. Tominaga Y, Kazuaru U, Toshihito H, et al: More than 1000 cases of parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 38(Suppl):S168–S171, 2001 22. Tagaki H, Tominaga Y, Uchida K, et al: Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 200:18–23, 1984 23. Klempa I, Frei U, Rotter P, et al: Parathyroid autograft morphology and function: six year’s experience with parathyroid autotransplantation in uremic patients. World J Surg 8:540–546, 1984 24. Korcets Z, Magen H, Kraus L, Bernheim J: Total parathyroidectomy with autotransplantation in haemodialysis patients with secondary hyperparathyroidism-should it be abandoned? Nephrol Dial Transplant 21:341–346, 1987

25. Frei U, Klempa I, Schneider M, et al: Proc Eur Dial Transplant Assoc 18:548–553, 1981 26. De Francisco ALM, Amado JA, Casanova D et al: Recurrence of hyperparathyroidism after total parathyroidectomy with autotrasplantation: A new technique to localize the source of hormone excess. Nephron 58:306–309, 1991 27. Kaye M, Rosenthall L, Hill RO, Tabah RJ: Long term outcome following total parathyroidectomy in patients with end stage renal disease. Clin Nephrol 39:192–197, 1993 28. Ljutic D, Cameron JS, Ogg CS, et al: Long-term follow-up after total parathyroidectomy without parathyroid reimplantation in chronic renal failure. Quart J Med 87:685–692, 1994 29. Stracke S, Jehle P, Sturm D, et al: Clinical course after total parathyroidectomy without autotransplantation in patients with end stage renal failure. Am J Kidney Dis 33:304–311, 1999 30. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of the World Health Organization Study Group, Geneva, World Health Organization, 1994 31. Chou FF, Chen JB, Lee CH, et al: Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism. Arch Surg 136:1064–1068, 2001 32. Heaf H: Causes and consequences of adynamic bone disease. Nephron 88: 97–106, 2001 33. Sherrard DJ, Hercz G, Pei Y, et al: The spectrum of bone disease in end stage renal failure: an evolving disorder. Kidney Int 43:436– 442, 1993 34. Torres A, Lorenzo V, Hernandez D, et al: Bone disease in predialysis, hemodia´lisis and CAPD patients: Evidence of a better bone response to PTH. Kidney Int 47:1434–1442, 1995 35. Andress D, Maloney N, Endres D, Sherrard D: Aluminium associated bone disease in chronic renal failure. J Bone Miner Res 1:391–398, 1986 36. Hercz G, Pei Y, Greenwood C, et al: Aplastic osteodystrophy without aluminum: the role of “suppressed” parathyroid function. Kidney Int 44:860–866, 1993 37. Cannata J: Hypokinetic azotemic osteodystrophy. Kidney Int 54:1000–1016, 1998 38. Coco M, Rush H: Increased. Am J Kidney Dis 36:1115–1121, 2000 39. Mucsi I, Hercz G: Adynamic bone disease: Pathogenesis, diagnosis and clinical relevance. Curr Opin Nephrol Hypertens 6:356– 361, 1997 40. Atsumi K, Kushida K, Yamazaki K, et al: Risk factors for vertebral fractures in renal osteodystrophy. Am J K Dis 33:287–293, 1999 41. Mawad HW, Sawaya BP, Sarin R, Malluche HH: Calcific uremic arteriolopathy in association with low turnover uremic bone disease. Clin Nephrol 52:160–166, 1999 42. Davies MR, Hruska KA: Pathophysiological mechanisms of vascular calcification in end stage renal disease. Kidney Int 60:472– 479, 2001 43. Guerin AP, London GM, Marchais SJ, Metivier F: Arterial stiffening and vascular calcifications in end stage renal disease. Nephrol Dial Transplant 15:1014–1021, 2000 44. Scho¨mig M, Ritz E: Management of disturbed calcium metabolism in uremic patients. 2 Indications for parathyroidectomy. Nephrol Dial Transplant 15(Suppl 5):25–29, 2000