Several studies showed that all medications currently used as phosphate binders are effective in lowering serum phosphorus levels. All these medications should be administered with the food to bind phosphate in the gastrointestinal tract. Aluminum hydroxide (labeled use as a gastric antacid medication) is a potent, low cost, phosphate binder, but concern about skeletal, hematological, and neurological toxicity led to a preferential use of calcium salts (carbonate and acetate) in the 1990s [26]. The most severe cases of aluminum toxicity occurred in patients whose dialysate was contaminated with aluminum, and that aluminum-based binders only played a secondary role. Moreover, the quantity of aluminum-based phosphate binders that is safe is unknown, therefore, as numerous alternative phosphate binders have become available, the long-term use of aluminum-based phosphate binders should be avoided.

The use of large doses of calcium-containing phosphate binders subsequently led to concerns about calcium overload because of a potential for generating a positive calcium balance, then new calcium-free phosphate binders were introduced, as sevelamer-HCl, sevelamer carbonate, and lanthanum carbonate. Some papers, comparing the use of sevelamer with the use of calcium-based salts, have shown to attenuate progression of arterial calcification in patients with chronic kidney disease stages 3–5 [27] and stage 5D [28, 29]. However, other more recent randomized controlled trials have not reproduced these results and have found high and similar rates of progression of vascular calcification in patients receiving sevelamer-HCl as compared with those receiving calcium acetate [30, 31].

Recently some authors reported reduction in death for all causes and for cardiovascular disease in incident hemodialysis patients treated with sevelamer versus calcium carbonate [32]. Guidelines suggest restricting the dose of calcium-based phosphate binders in the presence of arterial calcification, adynamic bone disease or if serum PTH levels are persistently low.

In efforts to control hyperphosphatemia, dialysis regimens that allow an increase in phosphate removal may be an alternative in patients who cannot tolerate phosphate binders or are not willing to take sufficient amounts of them.

Nocturnal prolonged-duration hemodialysis, or daily (six times weekly), found significant decreases in serum phosphorus compared to standard hemodialysis given thrice weekly for 4 hours each session.

The renal population usually show low serum calcium levels as a consequence of vitamin D deficit. Guidelines [21] suggest that total serum calcium level, corrected for serum albumin level, should be maintained in the normal range (2.10–2.37 mmol/L) administering vitamin D sterols and calcium salt not close to mealtimes. In hemodialysis patients, serum calcium levels are corrected by calcium into dialysate. In the presence of persistent or recurrent hypercalcemia, it is strongly recommended that the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog be restricted.

KDIGO guidelines provide a suggestion to maintain PTH levels into the range of normality in chronic kidney disease stages 3–5 and between 2 and 9 times the normal range in chronic kidney disease stage 5D [21]. Active vitamin D receptor activators (VDRA) are one of the classic therapies suggested to achieve those PTH targets, by direct mechanism on VDRA expressed on parathyroid glands, and by indirect pathway, increasing serum calcium levels. Calcitriol (1,25-dihydroxyvitamin D₃) is the natural VDRA historically adopted orally or intravenously each dialysis session to control PTH targets in renal patients. Classical side effects are hypercalcemia and hyperphosphatemia, due to increased intestinal absorption. Recently, four vitamin D analogs have been introduced in the nephrologic arena, namely, alfacalcidol, doxercalciferol, paricalcitol and oxacalcitriol.

Paricalcitol, derived from the side chain modification, elicits a selective activation of the VDRs expressed at the parathyroid gland with a lesser effect on those expressed in the intestinal tract [33]. Paricalcitol is administered orally or intravenously at the end of the dialysis session, and it has shown promising results in PTH value suppression in chronic kidney disease stage 2–5 [34]. Cinacalcet, the only clinically available calcimimetic agent, mimics an increase in levels of extracellular calcium, augmenting the signal caused by the binding of extracellular ionized calcium to CaSR (calcium sensor in parathyroid glands, cloned in 1993 [35]) to increase intracellular calcium and decrease PTH release; cinacalcet does not enhance intestinal calcium and phosphorus absorption.

Cinacalcet in secondary hyperparathyroidism treatment is approved only for dialysis population. Initial dosage is 30 mg/day orally, with titration up to the maximum dosage of 180 mg/day. As the main adverse event is hypocalcemia, its use is frequently associated with vitamin D analogs and calcium supplements. Weekly serum level check is requested. Nausea and vomiting are others of the most frequently reported adverse events in studies [36–38].

Emerging evidence of several pleiotropic effects related to the activation of the VDR is transforming the use of vitamin D sterols among nephrologists. Regardless of the PTH level, ergocalciferol, cholecalciferol, and calcifediol (nutritional vitamin D) are currently prescribed to replenish lower levels of circulating 25-(OH)-vitamin D when levels fall under 30 ng/mL in the community, as well as in chronic kidney disease and dialysis patients.

The early replenishment of nutritional vitamin D deficiency could be preventive, delaying the further onset and evolution of secondary hyperparathyroidism.