Recent clinical studies evaluated a novel SHPT therapy, the extended-release calciferol (ERC), which gradually increases serum total 25-hydroxyvitamin D (14, 15, 18). According to the latest results, a once daily dose ERC provided gradual rise of 25-hydroxyvitamin D, resulting in a physiologically controlled increase in serum 1,25D and a sustained reduction of PTH in patients with CKD stages 3 to 4, with minimal effects on serum calcium and phosphate levels, suggesting that it is a safe and effective treatment option for SHPT in CKD patients (15, 18). An especially important observation was that ERC therapy produced 25-hydroxyvitamin D level dependent reductions in plasma iPTH and bone turnover markers when mean serum total 25-hydroxyvitamin D reached at least 50.8 ng/mL, indicating that CKD patients may require higher vitamin D target levels than those currently recommended (19). Furthermore, ERC exhibited similar encouraging efficacy results with a favorable safety profile in a real world setting as in the clinical trials (20). Of note, ERC is currently licensed in the USA and Canada, but marketing authorization is pending for countries in Europe.
Effective control of hyperphosphatemia: the phosphate-protein dilemma
Disorders of mineral metabolism are well-known and potentially modifiable risk factors for all-cause and cardiovascular mortality in dialysis patients (21-23). An especially strong association has been observed between mortality and high serum phosphorus levels in these patients, calling for special consideration in the management of hyperphosphatemia. The KDOQI guidelines recommend target serum phosphorus levels between 1.1 and 1.78 mmol/l (3.5-5.5 mg/dl), while KDIGO guidelines suggest even lower upper threshold (7, 23). Interestingly, low phosphorus levels are observed in older hemodialysis patients, in whom it is associated with increased mortality, thus raising the question of whether this was an effect of lower protein intake which is commonly associated with older age (24). Furthermore, it seems that residual kidney function also has a substantial impact on the mortality risk associated with serum phosphorus among HD patients, with higher residual renal urea clearance associated with higher serum phosphorus and higher mortality (25).
The knowledge about the mechanisms involved in phosphorus homeostasis in CKD patients is constantly improving. In healthy persons, about 60 to 80% of ingested phosphorus is absorbed through the gastrointestinal tract, and most of it is removed by the kidneys. However, in dialysis patients, phosphorus absorption is difficult to quantitate as the dialysis treatments complicate metabolic balance studies (26). Furthermore, vitamin D therapy and hyperparathyroidism also have an important effect on the absorption rate (27, 28).
The currently recommended daily phosphorus intake is 1000mg for healthy persons, and <800mg for CKD patients (27). The main food sources of phosphorus are the protein-rich food groups, including dairy products, meat, and fish, thus emphasizing the important liaison between protein intake and phosphorus burden (29). Namely, to comply with the recommended daily phosphorus intake of <800mg, one should only ingest 50-60g of protein per day. This may represent a challenge for some patients, as recommended protein intake for dialysis patients is >1g/kg/day. In addition to the absolute amount of dietary phosphorus, its type (organic versus inorganic) and source (animal versus plant-derived) may also be important (Figure 1). The rate of phosphorus absorption varies from 20-40% from plant-based sources, to 40-60% from animal proteins. Inorganic phosphorus, present in processed, preserved, or enhanced foods or soft drinks that contain additives, in which phosphorus is not bound to proteins, is much more readily absorbed, at a rate of 90 to 100%. The main implication of this for patient management is that the phosphorus burden from food additives may be disproportionately higher relative to organic sources, thus shifting the focus from the strict protein restriction to avoiding processed food (29).