**5. Parathyroidectomy**

340 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Calcitriol 1,25(OH)2D3; natural hormone oral 0.25 µg

Alfacalcidol 1(OH)D3; synthetic prohormone oral 0.5 µg

Doxercalciferol 1(OH)D2, synthetic prohormone oral 2.5 µg

Paricalcitol 19nor-1,25(OH)2D2; synthetic analogue oral 1 µg

(Oxacalcitriol) 22oxa-1,25(OH)2D;3; synthetic analogue NA

Table 3. Characteristics and oral calcitriol equivalent doses of vitamin D receptor activators

Calcimimetics are allosteric modulators of the calcium sensing receptor that sensitize the receptor to extracellular calcium. This results in reduced PTH secretion and inhibited parathyroid cell proliferation (Nemeth et al., 1998; Chin et al., 2000). This decrease in serum PTH is accompanied by control of serum calcium and phosphorus levels in patients with sHPT as well as a halt or regression of parathyroid gland hyperplasia (Meola et al., 2009). Initial phase III trials and various observational studies have shown that cinacalcet enables more patients to reach the recommended biochemical targets (Block et al., 2004; Lindberg et al., 2005; Urena et al., 2009) and allows sustained biochemical control for long term up to 3 years (Sprague et al., 2009). At present cinacalcet hydrochloride is the only calcimimetic available for clinical use. In contrast to VDRA, cinacalcet decreases all three important biochemical parameters of CKD-MBD (PTH, phosphorus, calcium) (Urena et al., 2009). In addition to excellent results on laboratory parameters, cinacalcet has also shown favourable effects on cardiovascular hospitalization, bone fracture rate, parathyroidectomy rate and quality of life (Cunningham et al., 2005). In a prospectively designed observational study use of cinacalcet on top of standard sHPT therapy with VDRA and phosphate binders resulted in a 26% lower all-cause mortality and a 24% lower cardiovascular mortality than in patients without cinacalcet, with the largest survival benefit for patients with most severe sHPT (PTH >600 pg/mL) (Block et al., 2010). The ongoing double-blind, randomised placebo-controlled EVOLVE trial (Evaluation of cinacalcet HCl therapy to lower cardiovascular events) currently determines whether cinacalcet reduces all-cause mortality

Generally, initial therapy starts with a daily dose of 30 mg followed by dose-titration every 2 to 4 weeks if necessary. Serum calcium levels must be monitored regularly because of its

Whereas VDRA reduce PTH gene transcription and hormone synthesis over a period of several hours or even days, cinacalcet inhibits PTH secretion within minutes, with a maximal decrease occurring within 2 to 4 hours after administration. Besides gastrointestinal side effects, hypocalcemia is one of the most common adverse events seen with cinacalcet. It is thought to occur after decreased mobilization of calcium from bone

**Oral calcitriol equivalent dose (thrice weekly)** 

intravenous 0.5 µg

intravenous 1 µg

intravenous 5 µg

intravenous 2 µg

**VDRA Chemical structure** 

Maxacalcitol

**4. Calcimimetics** 

(VDRA). Abbreviation: NA, not available.

or non-fatal cardiovascular events (Chertow et al., 2007).

known hypocalcemic effect.

Persistently increased serum PTH levels >800 pg/mL (88.0 pmol/L) in presence of hypercalcemia or hyperphosphatemia refractory to medical therapy and calcific uremic arteriolopathy (calciphylaxis) with concomitantly elevated PTH levels are an indication for surgery (KDOQI, 2003; KDIGO, 2009). Subtotal and total parathyroidectomy (PTX) with or without forearm autograft arose as a treatment option in the 1990s (Tominaga et al., 1997) and PTX continues to be a primary therapeutic option for refractory sHPT in both Europe and the US. Rates of PTX increased for US patients on hemodialysis from 1998 to 2002 despite an increase in therapeutic options (Foley et al., 2005). The frequency of PTX across Europe has remained relatively stable since the mid-1980s (Malberti et al., 2001) and is lower in older patients (Pelletier et al., 2010).

PTX effectively decreases PTH, calcium and phosphorus and offers the highest percentage cure for sHPT, compared to all other medical and surgical treatments. However, recurrent hyperparathyroidism can be observed in 10 - 70% of patients dependent on follow-up time (Johnson et al., 1988; Gagne et al., 1992; Gasparri et al., 2001). For total parathyroidectomy with autotransplantation an intra-operative selection of parathyroid tissue with diffuse hyperplasia but low proliferative potential (and exclusion of nodular tissue) is feasible and minimizes the risk of graft-dependent recurrent hyperparathyroidism (Neyer et al., 2002). Alternatively to surgery, ultrasound-guided percutaneous fine-needle ethanol injection into nodular hyperplastic parathyroid glands is very common in Japan (Giangrande et al., 1992; Kitaoka et al., 1994; Fukagawa et al., 1999). Apart from ethanol, also calcitriol or novel VDRA can be directly placed into enlarged parathyroid glands using the same technique (Shiizaki et al., 2003).

To date no specific guidelines considering sHPT treatment in hemodialysis patients on kidney transplant waiting list have been established. After successful kidney transplantation persistent HPT can be observed in up to 25% of patients one year after transplantation despite adequate renal graft function. Severity of sHPT at time of transplantation was found to be a significant indicator of persistent HPT (Evenepoel et al., 2004). If indicated, therapy for persistent HPT should be initiated about three months after renal transplantation because further spontaneous improvement thereafter is rare. Because this special situation of persistent HPT after transplantation is usually accompanied by hypercalcemia and hypophosphatemia, conventional therapy with phosphate binders, VDRA or calcium supplements is not indicated in most patients. Therefore, PTX is the preferred treatment option in this situation and has been shown to be effective, safe, though associated with a mild deterioration of graft function in the early postoperative phase but similar graft survival in the long-term compared to kidney transplant patients without PTX and linked to a blood pressure and lipid lowering effect (Triponez et al., 2008). Recently, also cinacalcet has been proposed to offer an alternative therapeutic option to PTX, although not approved

Management of Secondary Hyperparathyroidism in Hemodialysis Patients 343

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Block, G. A., Hulbert-Shearon, T. E., Levin, N. W., & Port, F. K. (1998). Association of serum

hemodialysis patients: a national study. *Am J Kidney Dis* 31(4): pp. 607-617 Block, G. A., Klassen, P. S., Lazarus, J. M., Ofsthun, N., Lowrie, E. G., & Chertow, G. M.

Block, G. A., Martin, K. J., de Francisco, A. L., Turner, S. A., Avram, M. M., Suranyi, M. G.,

Block, G. A., Zaun, D. Smits, G., Persky, M., Brillhart, S., Nieman, K., Liu, J., & St Peter, W. L.

Block, G. A., Zeig, S., Sugihara, J., Chertow, G. M., Chi, E. M., Turner, S. A., & Bushinsky, D.

Brossard, J.H., Lepage, R., Cardinal, H., Roy, L., Rousseau, L., Dorais, C., & D'Amour, P.

Chertow, G. M., Blumenthal, S., Turner, S., Roppolo, M., Stern, L., Chi, E. M., & Reed, J.

Chertow, G. M., Pupim, L. B., Block, G. A., Correa-Rotter, R., Drueke, T. B., Floege, J.,

Chin, J., Miller, S. C., Wada, M., Nagano, N., Nemeth, E. F., & Fox, J. (2000). Activation of the

hyperparathyroidism in uremic rats. *J Am Soc Nephrol* 11(5): pp. 903-11 Covic, A., Kothawala, P., Bernal, M., Robbins, S., Chalian, A., & Goldsmith, D. (2009).

(PTH) detected by intact PTH assays. *Clin Chem* 46(5): pp. 697-703

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hyperphosphataemia in children with chronic kidney disease. *Nephrol Dial* 

long-term effects of lowering dialysate calcium concentration. *Kidney Int* 43(3): pp.

phosphorus and calcium x phosphate product with mortality risk in chronic

(2004). Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.

Hercz, G., Cunningham, J., Abu-Alfa, A. K., Messa, P., Coyne, D. W., Locatelli, F., Cohen, R. M., Evenepoel, P., Moe, S. M., Fournier, A., Braun, J., McCary, L. C., Zani, V. J., Olson, K. A., Drueke, T. B., & Goodman, W. G. (2004). Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. *N Engl J Med* 

(2010). Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients. *Kidney Int* 78(6):

A. (2008). Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. *Nephrol Dial* 

(2000). Influence of glomerular filtration rate on non-(1-84) parathyroid hormone

(2006). Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. *Clin* 

Goodman, W. G., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Albizem, M., Olson, K., Klassen, P., & Parfrey, P. (2007). Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design

calcium receptor by a calcimimetic compound halts the progression of secondary

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for the use in this situation and cost-intensive if used for many years (Kruse et al., 2005; Serra et al., 2005; Srinivas et al., 2006; Zitt et al., 2007).

Therefore, we believe that a good and early control of sHPT prior to kidney transplantation is mandatory. This should be initially done using all medical options including cinacalcet, but if unsuccessful in control of severe sHPT proceeding straight to PTX for an optimal and cost-effective treatment. Randomized clinical trials directly comparing medical with surgical therapy of sHPT are lacking.

To avoid severe postoperative hypocalcemia ("hungry bone syndrome), pre-/peri- and postoperative calcium and calcitriol supplementation (e.g. 1 to 2 g elemental calcium thrice a day, 1 to 4 µg calcitriol per day; parenteral calcium substitution if symptomatic hypocalcemia is present with 1 to 2 mg elemental calcium/kg/h) must be guaranteed along with frequent controls of serum calcium levels. In case of recurrent or persistent hyperparathyroidism after parathyroidectomy, cinacalcet has been shown to be a viable and safe treatment option (Zitt et al., 2010).
