**3.1 Correction of vitamin D deficiency and insufficiency**

Neither the normal nor the desirable target ranges for 25-hydroxyvitamin D (25(OH)D) levels are known in patients on hemodialysis. In accordance with patients without chronic kidney disease, 25(OH)D levels <12.5 ng/mL (<30 nmol/L) are defined as vitamin D deficiency, values <30 ng/mL (<75 nmol/L) as vitamin D insufficiency. Observational studies have shown an association between low 25(OH)D levels and adverse clinical outcomes (Holick, 2005; Wolf et al., 2007; Giovannucci, 2008). Although data from clinical trials are missing to show a survival benefit after increasing 25(OH)D levels in insufficient or deficient hemodialysis patients, current guidelines suggest to replete 25(OH)D stores in these patients on grounds of low costs, relative safety of repletion and potential therapeutic impact (KDIGO, 2009). After initial measurement and diagnosis of vitamin D deficiency, a supplementation using cholecalciferol or ergocalciferol may be initiated with remeasurement after 3 months of supplementation. There are no data regarding the choice of vitamin D product or the administration route. Altogether, oral repletion seems to be more favourable compared to intramuscular route in hemodialysis patients. In accordance with the general population a daily dose of 1000 to 2000 IU of cholecalciferol or a corresponding weekly dose are given (KDOQI, 2003; KDIGO, 2009; Uhlig et al., 2010). In a recent study in 107 hemodialysis patients, 91% of the patients had a serum 25(OH)D level higher than the target level of 75 nmol/L (30 ng/mL) after 3 months of monthly oral substitution of 100,000 IU (at first dialysis session of the month) (Jean et al., 2009). This approach seems to be safe and guarantee patient compliance. If hypercalcemia or hyperphosphatemia occurs, vitamin D repletion should be temporarily discontinued or abandoned. Table 2 gives an overview of the key differences between 25(OH)D and its "active" form 1,25(OH)2D.


Table 2. Characteristics and differences of 25(OH)D and 1,25(OH)2D. Abbrevations: VDR, vitamin D receptor.

### **3.2 Vitamin D receptor activators**

338 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Dialytic methods to improve phosphorus removal include prolonged (nocturnal) hemodialysis (Culleton et al. 2007; Walsh et al., 2010) and convective strategies (Tonelli et

Neither the normal nor the desirable target ranges for 25-hydroxyvitamin D (25(OH)D) levels are known in patients on hemodialysis. In accordance with patients without chronic kidney disease, 25(OH)D levels <12.5 ng/mL (<30 nmol/L) are defined as vitamin D deficiency, values <30 ng/mL (<75 nmol/L) as vitamin D insufficiency. Observational studies have shown an association between low 25(OH)D levels and adverse clinical outcomes (Holick, 2005; Wolf et al., 2007; Giovannucci, 2008). Although data from clinical trials are missing to show a survival benefit after increasing 25(OH)D levels in insufficient or deficient hemodialysis patients, current guidelines suggest to replete 25(OH)D stores in these patients on grounds of low costs, relative safety of repletion and potential therapeutic impact (KDIGO, 2009). After initial measurement and diagnosis of vitamin D deficiency, a supplementation using cholecalciferol or ergocalciferol may be initiated with remeasurement after 3 months of supplementation. There are no data regarding the choice of vitamin D product or the administration route. Altogether, oral repletion seems to be more favourable compared to intramuscular route in hemodialysis patients. In accordance with the general population a daily dose of 1000 to 2000 IU of cholecalciferol or a corresponding weekly dose are given (KDOQI, 2003; KDIGO, 2009; Uhlig et al., 2010). In a recent study in 107 hemodialysis patients, 91% of the patients had a serum 25(OH)D level higher than the target level of 75 nmol/L (30 ng/mL) after 3 months of monthly oral substitution of 100,000 IU (at first dialysis session of the month) (Jean et al., 2009). This approach seems to be safe and guarantee patient compliance. If hypercalcemia or hyperphosphatemia occurs, vitamin D repletion should be temporarily discontinued or abandoned. Table 2 gives an overview of the key differences between 25(OH)D and its

**25(OH)D 1,25(OH)2D** 

30 to 50 pg/mL (75 to 125 pmol/L)

30 to 50 ng/mL (75 to 125 nmol/L)

values) 1000 1

protein (relative values) 1000 1 Free concentration (relative values) 1 1 Half-life 25 to 30 days 4 to 8 hours VDR affinity (relative values) 1 500 to 1000

Table 2. Characteristics and differences of 25(OH)D and 1,25(OH)2D. Abbrevations: VDR,

**2.3 Dialytic methods for phosphorus removal** 

**3.1 Correction of vitamin D deficiency and insufficiency** 

al., 2009).

**3. Vitamin D therapy** 

"active" form 1,25(OH)2D.

Total plasma concentration (recommended normal values)

vitamin D receptor.

Total plasma concentration (relative

Binding affinity to vitamin D-binding

Treatment of sHPT with active vitamin D receptor activators (VDRA) is a well established therapeutic modality, and current practice guidelines recommend to treat patients with elevated and/or increasing PTH levels with a VDRA (KDIGO, 2009). Observational studies are indicating a survival benefit of VDRA in hemodialysis patients in comparison with patients without VDRA treatment (Teng et al., 2003, 2005; Tentori et al., 2006; Naves-Diaz et al., 2008). Again, prospective controlled randomised clinical trials indicating a benefit on patient-level clinical outcomes with VDRA therapy are missing but strongly awaited. Calcitriol, the physiological VDRA, is the natural regulator of parathyroid gland function and growth and exerts its effect on PTH secretion by inhibiting mRNA synthesis through its action on the vitamin D receptor (VDR), a highly specific receptor that acts as a transcription factor. In addition, calcitriol is able to inhibit PTH secretion by increasing calcium absorption in the intestine, while also increasing bone resorption and, consequently, calcium release from bone. Moreover, calcitriol regulates the expression of its own receptor, stimulating its synthesis. The deficit of calcitriol observed in hemodialysis patients as well as a transformation into nodular hyperplasia with progressive sHPT is associated with a decrease in VDR levels in the parathyroid gland. Decreased VDR expression may than cause resistance to VDRA. VDRA generally control sHPT well in patients with moderately increased hypertrophic glands and less well in patients with enlarged hyperplastic glands and should therefore be started early in the development of sHPT (Cunningham et al., 2011). Beyond the classical endocrine effects on parathyroid gland, bone and intestine, the pleiotropic paracrine and autocrine effects of vitamin D have been associated with improvement of cardiovascular risk factors, including increased renin activity, hypertension, inflammation, insulin resistance, diabetes, albuminuria and an improved immune response.

Besides the native active hormone calcitriol (1,25(OH)2D3), the two prodrugs alfacalcidol (1(OH)D3) and doxercalciferol (1(OH)D2) and the two vitamin D analogues paricalcitol (19 nor-1,25(OH)2D2) and maxacalcitol (22-oxa-1,25(OH)2D3) can be used. Paricalcitol and maxacalcitol (oxacalcitriol) bind directly to the VDR, whereas doxercalciferol and alfacalcidol need an enzymatic 25-hydroxylation activation step in the liver. So far no prospective, placebo-controlled and blinded clinical trial involving 22-oxacalcitriol, paricalcitol, or doxercalciferol has yet demonstrated additional clinical benefits when compared with calcitriol, nor have any studies been published showing that either calcitriol or alfacalcidol has an advantage over the other with respect to biochemical or clinical end points (Cunningham & Zehnder, 2011). Therefore, low dose therapy with calcitriol (e.g. 0.25 µg/d orally or 0.25 µg thrice weekly orally or intravenously as a starting dose) is recommended with elevated or increasing PTH levels (KDIGO, 2009). Characteristics and oral calcitriol equivalent doses of various available VDRA are presented in Table 3.

According to current practice guidelines, the target range for PTH is now 2-9 times the upper limit of the normal range (KDIGO, 2009; Uhlig et al., 2010; Goldsmith et al., 2010). This wide range takes into account a significant interassay variability of values obtained with different commercial PTH assays (Koller et al., 2004; Souberbielle et al., 2010), inability to uniformly predict bone histologic and histomorphometric states by means of PTH within this range and the epidemiological observation of increased all-cause mortality starting from PTH values >400 to 600 pg/mL (Uhlig et al., 2010). If there is no successful response with PTH reduction into the suggested target range, or dose-limiting side effects occur, especially hypercalcemia and hyperphosphatemia, a calcimimetic can be initiated instead or combined with a low dose of VDRA.

Management of Secondary Hyperparathyroidism in Hemodialysis Patients 341

caused by lowered PTH levels. In most patients, this hypocalcemia can be successfully managed with dose adjustments or a combination with low doses of VDRA in patients with moderate to severe sHPT. Clinical trials have demonstrated the superior suppression of PTH production and control of calcium and phosphorus in hemodialysis patients who use cinacalcet, both as adjunctive therapy to VDRA and as primary therapy with reduced doses of VDRA , compared with sHPT therapy with VDRA and phosphate binders only (Chertow

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

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

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

et al., 2006; Block et al., 2008; Fishbane et al., 2008; Messa et al., 2008).

**5. Parathyroidectomy** 

(Shiizaki et al., 2003).

in older patients (Pelletier et al., 2010).


Table 3. Characteristics and oral calcitriol equivalent doses of vitamin D receptor activators (VDRA). Abbreviation: NA, not available.
