**1. Introduction**

330 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Takeda E, Taketani Y, Morita K, Tatsumi S, Katai K, Nii T, Yamamoto H, Miyamoto K.

Takeda E, Taketani Y, Nashiki K, Nomoto M, Shuto E, Sawada N, Yamamoto H, Isshiki M.

Tenenhouse HS. (2006) Regulation of phosphorus homeostasis by the type IIa

US Renal Data System Annual Data Report Bethesta (2005) *National Institutes of Health* 

Vaithilingam I, Polkinghorne KR, Atkins RC, Kerr PG. (2004) Time and exercise improve phosphate removal in hemodialysis patients. *Am J Kidney Dis.* 43(1): 85-89. Wang AY, Wang M, Woo J, Lam CW, Li PK, Lui SF, Sanderson JE. (2003) Cardiac valve

Wei M, Taskapan H, Esbaei K, Jassal SV, Bargman JM, Oreopoulos DG. (2006) K/DOQI

Willett WC, Buzzard M. (1998) *Nature of Variation in Diet in Nutritional Epidemiology,* 2nd Ed., edited by Willett WC, New York, Oxford University Press, pp33-49. Xu H, Bai L, Collins JF, Ghishan FK. (2002) Age-dependent regulation of rat intestinal type

Yoshida T, Fujimori T, Nabeshima Y. (2002) Mediation of unusually high concentrations of

expression of renal 1 alpha-hydroxylase gene. Endocrinology 143: 683–689. Young EW, Akiba T, Albert JM, McCarthy JT, Kerr PG, Mendelssohn DC, Jadoul M. (2004)

Young EW, Albert JM, Satayathum S, Goodkin DA, Pisoni RL, Akiba T, Akizawa T,

Yu X, White KE. (2005) Fibroblast growth factor 23 and its receptors. *Ther Apher Dial* 9: 308–

Yu X, White KE. (2005) FGF23 and disorders of phosphate homeostasis. Cytokine Growth

Zoccali C. (2000) Cardiovascular risk in uraemic patients – Is it fully explained by classical

risk factors? *Nephrol. Dial. Transplant.* 15: 454–457.

*Adv Enzyme Regul* 40: 285-302.

*Nephrol.* 14: 159–168.

*Nephrol.* 38: 739-743.

*Physiol* 282: C487–C493.

44(Suppl 2): 34-38.

312.

*Kidney Int.* 67: 1179–1187.

Factor Rev 16: 221–232.

pathways. *Adv Enzyme Regul* 46: 154–161.

Na/phosphate cotransporter. *Annu Rev Nutr* 25: 197–214.

*National Institute of Diabetes and Digestive and Kidney Diseases.*

(2000) Molecular mechanisms of mammalian inorganic phosphate homeostasis.

(2006) A novel function of phosphate-mediated intracellular signal transduction

calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study. *J. Am. Soc.* 

guideline requirements for calcium, phosphate, calcium phosphate product, and parathyroid hormone control in dialysis patients: can we achieve them? *Int Urol* 

IIb sodium-phosphate cotransporter by 1,25-(OH2) vitamin D3. *Am J Physiol Cell* 

1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased

Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). *Am J Kidney Dis.*

Kurokawa K, Bommer J, Piera L, Port FK. (2005) Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study. Secondary hyperparathyroidism (sHPT) represents the adaptive and very often finally maladaptive response of the organism to control the disturbed homeostasis of calcium, phosphorus and vitamin D metabolism caused by declining renal function. Dysregulation of calcium and phosphorus homeostasis leads to elevated levels of the phosphatonin fibroblast growth factor 23 (FGF23), decreased renal phosphorus excretion, increased serum phosphorus, and diminished synthesis of calcitriol (1,25(OH)2D3), the active form of vitamin D. These alterations result in increased secretion and synthesis of parathyroid hormone (PTH) and parathyroid cell hyperplasia (Cunningham et al., 2011).

Evidence is available that these disturbances in mineral metabolism lead to vascular (Goodman et al., 2000; Raggi et al., 2002) and valvular (Ribeiro et al., 1998) calcifications and are directly linked to an increased risk of cardiovascular morbidity and mortality as well as excess all-cause mortality (Covic et al., 2009). In accordance to a recent systematic review, the risk of cardiovascular and all-cause mortality is greatest with elevated serum phosphorus followed by increased serum calcium and PTH (Covic et al., 2009). Apart from extra-skeletal side effects, sHPT also leads to profound alterations in bone metabolism which become obvious in the different forms of renal osteodystrophy (Malluche & Faugere, 1990; Moe et al., 2006). This clinical syndrome encompassing mineral, bone and cardiovascular abnormalities has been termed CKD-related Mineral and Bone Disorder (CKD-MBD) (Moe et al., 2006). Furthermore, sHPT is thought to play a role in various other complications of end-stage renal disease as bone pain, bone fractures, muscle dysfunction, sexual dysfunction, disturbed hematopoiesis, immune dysfunction, pruritus and calcific uremic arteriolopathy (calciphylaxis) (Rodriguez & Lorenzo, 2009). An overview of the current understanding of the pathogenesis of sHPT is given in Figure 1.

In an attempt to improve clinical care, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQITM [KDOQI]) has recommended target ranges for serum intact PTH, serum phosphorus and total corrected serum calcium (KDOQI, 2003). More recently, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for diagnosis, evaluation, prevention and treatment of CKD-MBD have been published (KDIGO, 2009) and endorsed by the US KDOQI (Uhlig et al., 2010) and European Renal Best Practice (Goldsmith et al., 2010) groups. These latter guidelines have tried to provide evidence-based recommendations, but due to the very limited availability of high quality

Management of Secondary Hyperparathyroidism in Hemodialysis Patients 333

The 84-amino-acid peptide hormone PTH has a very short half-life of two to four minutes after parathyroid secretion. It is metabolized to shorter fragments in the liver which are then excreted by the kidneys. With increasing renal failure and progressive CKD the proportion of these fragments with a 5 to 10 times longer half-life raises due to decreased renal clearance. Although the exact composition and possible function of the various PTH fragments are not yet fully elucidated, experimental data clearly found a clinically relevant biological activity of some of these fragments. Routinely used second-generation PTH assays, globally called "intact" PTH assays because they were thought to measure the fulllength PTH 1-84 molecule only, recognize with various cross-reactivities (from approximately 50 to 100%) a PTH fragment, which co-elutes in high-performance liquid chromatography with a synthetic PTH 7–84 fragment. With progressive renal failure the amount of this and related PTH fragments gradually increases from about 20% in healthy individuals to about 50% in hemodialysis patients (Brossard et al., 2000). Therefore, at least in part, the progressive increase in measured PTH with decreasing renal function is also linked to the decreased renal metabolism and clearance of PTH 1-84 and its fragments. The different commercially available second-generation PTH assays have variable crossreactivity with the PTH 7-84 fragment, therefore PTH measurements with different assays are not fully comparable and due to lacking standardization of PTH measurement sHPT patients might be classified differently according to KDOQI or KDIGO guidelines, resulting in different and due to misclassification potentially disadvantageous therapeutic interventions (Koller et al., 2004). Newer third-generation PTH assays, which show no crossreactivity with the PTH 7-84 and related fragments, have been developed. Unfortunately, in all bone biopsy studies, which were later used to establish the KDOQI and KDIGO PTH target ranges, the first available second-generation PTH assay was used, but this assay is no longer commercially available. In an attempt to provide some kind of comparability of PTH measurements and consistent classification, correcting factors for the different second-

generation PTH assays were proposed (Souberbielle et al., 2010).

cardiovascular health.

**2. Treatment of hyperphosphatemia** 

Current therapeutic strategies include the modification of calcium and phosphorus balance through restricted dietary calcium and phosphorus intake and removal during hemodialysis, administration of phosphate binders, vitamin D receptor activators (calcitriol and newer vitamin D analogues) and the calcimimetic cinacalcet, and ultimately parathyroidectomy in very severe sHPT. These interventions have been shown to improve the biochemical parameters (PTH, calcium, phosphorus), bone histology or histomorphometry and cardiovascular calcification, but still there is lacking evidence that improvements in these surrogate parameters translate into better patient outcomes. Traditionally interventions to treat sHPT primarily aimed at bone health, but over the years new experimental insights into cardiovascular calcification and epidemiological data about associated cardiovascular morbidity and mortality risk switched the emphasis from bone to

Declining renal function inevitably causes phosphorus retention due to decreased renal phosphorus clearance. This mechanism starts early in chronic kidney disease. However, hyperphosphatemia is prevented until the late stages of chronic kidney disease by an increase in FGF23 and PTH which control phosphorus homeostasis for a definite time. Initially, phosphorus retention stimulates FGF23 and PTH secretion, which in turn suppress

Fig. 1. Pathogenesis of secondary hyperparathyroidism. Declining kidney function causes reduced renal conversion of 25(OH)D to 1,25(OH)2D by CYP27B1 (25(OH)D-1-hydroxylase) and elevated serum phosphorus levels due to diminished phosphorus excretion. Increased phosphorus concentration, decreased calcium concentration and markedly reduced serum calcitriol levels lead to increased PTH synthesis and secretion in the parathyroid glands. Elevated FGF23 expression, to counteract the reduced phosphorus excretion, downregulates residual renal 25(OH)D-1-hydroxylase, additionally promoting the development of sHPT. These metabolic changes are accompanied by a variable downregulation and underexpression of the calcium-sensing receptor and vitamin D receptor on parathyroidal cells, rendering the parathyroid gland unable to respond appropriately to calcium and calcitriol. Dashed lines indicate counter-regulatory pathways. Abbreviations: FGF23, fibroblast growth factor 23; P, phosphorus; Ca2+, calcium; CaSR, calcium-sensing receptor; VDR, vitamin D receptor; FGFR1, fibroblast growth factor receptor 1, PTG, parathyroid gland.

clinical interventional trials with skeletal, cardiovascular or mortality end-points in this field, fewer and less mandatory recommendations are given compared to the older KDOQI guidelines.

The achievement of these target ranges set by the KDOQI or KDIGO guidelines is quite challenging (Young et al., 2004) and failure to reach these targets has been shown to be associated with increased risk for death compared to simultaneously achieving the targets for all three biochemical parameters PTH, calcium and phosphorus (Danese et al., 2008).

Fig. 1. Pathogenesis of secondary hyperparathyroidism. Declining kidney function causes reduced renal conversion of 25(OH)D to 1,25(OH)2D by CYP27B1 (25(OH)D-1-hydroxylase) and elevated serum phosphorus levels due to diminished phosphorus excretion. Increased phosphorus concentration, decreased calcium concentration and markedly reduced serum calcitriol levels lead to increased PTH synthesis and secretion in the parathyroid glands. Elevated FGF23 expression, to counteract the reduced phosphorus excretion, downregulates residual renal 25(OH)D-1-hydroxylase, additionally promoting the development of sHPT. These metabolic changes are accompanied by a variable downregulation and underexpression of the calcium-sensing receptor and vitamin D receptor on parathyroidal cells, rendering the parathyroid gland unable to respond appropriately to calcium and calcitriol. Dashed lines indicate counter-regulatory pathways. Abbreviations: FGF23, fibroblast growth factor 23; P, phosphorus; Ca2+, calcium; CaSR, calcium-sensing receptor; VDR, vitamin D receptor; FGFR1,

clinical interventional trials with skeletal, cardiovascular or mortality end-points in this field, fewer and less mandatory recommendations are given compared to the older KDOQI

The achievement of these target ranges set by the KDOQI or KDIGO guidelines is quite challenging (Young et al., 2004) and failure to reach these targets has been shown to be associated with increased risk for death compared to simultaneously achieving the targets for all three biochemical parameters PTH, calcium and phosphorus (Danese et al., 2008).

fibroblast growth factor receptor 1, PTG, parathyroid gland.

guidelines.

The 84-amino-acid peptide hormone PTH has a very short half-life of two to four minutes after parathyroid secretion. It is metabolized to shorter fragments in the liver which are then excreted by the kidneys. With increasing renal failure and progressive CKD the proportion of these fragments with a 5 to 10 times longer half-life raises due to decreased renal clearance. Although the exact composition and possible function of the various PTH fragments are not yet fully elucidated, experimental data clearly found a clinically relevant biological activity of some of these fragments. Routinely used second-generation PTH assays, globally called "intact" PTH assays because they were thought to measure the fulllength PTH 1-84 molecule only, recognize with various cross-reactivities (from approximately 50 to 100%) a PTH fragment, which co-elutes in high-performance liquid chromatography with a synthetic PTH 7–84 fragment. With progressive renal failure the amount of this and related PTH fragments gradually increases from about 20% in healthy individuals to about 50% in hemodialysis patients (Brossard et al., 2000). Therefore, at least in part, the progressive increase in measured PTH with decreasing renal function is also linked to the decreased renal metabolism and clearance of PTH 1-84 and its fragments. The different commercially available second-generation PTH assays have variable crossreactivity with the PTH 7-84 fragment, therefore PTH measurements with different assays are not fully comparable and due to lacking standardization of PTH measurement sHPT patients might be classified differently according to KDOQI or KDIGO guidelines, resulting in different and due to misclassification potentially disadvantageous therapeutic interventions (Koller et al., 2004). Newer third-generation PTH assays, which show no crossreactivity with the PTH 7-84 and related fragments, have been developed. Unfortunately, in all bone biopsy studies, which were later used to establish the KDOQI and KDIGO PTH target ranges, the first available second-generation PTH assay was used, but this assay is no longer commercially available. In an attempt to provide some kind of comparability of PTH measurements and consistent classification, correcting factors for the different secondgeneration PTH assays were proposed (Souberbielle et al., 2010).

Current therapeutic strategies include the modification of calcium and phosphorus balance through restricted dietary calcium and phosphorus intake and removal during hemodialysis, administration of phosphate binders, vitamin D receptor activators (calcitriol and newer vitamin D analogues) and the calcimimetic cinacalcet, and ultimately parathyroidectomy in very severe sHPT. These interventions have been shown to improve the biochemical parameters (PTH, calcium, phosphorus), bone histology or histomorphometry and cardiovascular calcification, but still there is lacking evidence that improvements in these surrogate parameters translate into better patient outcomes. Traditionally interventions to treat sHPT primarily aimed at bone health, but over the years new experimental insights into cardiovascular calcification and epidemiological data about associated cardiovascular morbidity and mortality risk switched the emphasis from bone to cardiovascular health.
