Identificación y delimitación de los yacimientos

Patient Mortality

In humans, there are well-documented benefits of active vitamin D therapy, such as control of secondary HPT, cure of osteomalacia and osteitis fibrosa cystica, demonstrated in studies using bone biopsies (Dusso et al. 2005, Olgaard and Lewin

2006). What is more, the recent study by Kovesdy compared the association between mortality and calcitriol treatment in patients undergoing and not undergoing dialysis (CKD stages 3-5) and concluded that therapy with 1,25(OH)2D significantly improved survival of non-dialysis patients (Kovesdy et al. 2008b).

The safe correction of 25(OH)D and 1,25(OH)2D deficiency are essential in

improvement of the outcomes in CKD (Dusso 2010). According to the current KDOQI guidelines for bone metabolism and CKD initial evaluation comprises assessment of calcium and phosphorus metabolism. If needed, the use of phosphate binders is recommended. Further, it is recommended to establish levels of 25(OH)D to prevent or treat insufficiency or deficiency. Levels of 25(OH)D <5 ng/ml or 12nM are indicative of severe vitamin D deficiency, 5-15 ng/ml or 12-37 nM indicate mild deficiency and those of 16-30 ng/ml or 40-75 nM – 25(OH)D insufficiency. Supplementation with vitamin D2 is normally initiated in all three cases (usually stages 3 and 4 CKD), as even in case of 25(OH)D insufficiency it has been shown to reduce the frequency and severity of secondary HPT. In patients with more advanced CKD (stage 5) and in those undergoing dialysis, ergocalciferol or cholecalciferol (i.e. the nutritional replacement) is not recommended as kidneys’ ability to generate 1,25(OH)2D is hugely reduced.

In stage 5 of CKD or in dialysis, guidelines recommend therapy with active vitamin D sterol, such as 1,25(OH)2D, alfacalcidol, paricalcitol or doxercalciferol. (Noordzij

et al. 2005) (KDIGO 2009). Treatment with active vitamin D sterols rapidly lowers PTH levels in the serum, improves hyperparathyroidism, bone disease and muskosceletal symptoms. Major side effect of active vitamin D sterols, including 1,25(OH)2D and alfacalcidol is increased intestinal absorption of calcium and

phosphorus, which leads to increased serum levels of those minerals, which eventually may contribute to hypercalcaemia, exacerbates hyperphosphotaemia and reduce bone formation (due to low PTH). In order to reduce or abolish these negative effects, novel analogues of 1,25(OH)2D have been developed (paricalcitol and doxercalciferol – available in USA; maxicalcitol and falecalcitol – available in Asia). Animal studies confirmed that maxicalcitol and paricalcitol are less calceamic and phosphataemic than 1,25(OH)2D, whilst effectively suppressing PTH (Nishii et al. 1991, Sjoden et al. 1984, Slatopolsky et al. 1995). Despite some advantages, none of the currently used vitamin D analogues has the ability to selectively target specific tissues, such as kidney or vasculature, instead they induce systemic changes triggered by the endocrine vitamin D system, which in consequence exacerbates the disease progression.

Observational studies demonstrate that both 1,25(OH)2D deficiency and toxicity are common in CKD, narrowing the therapeutic window. In terms of cardiovascular complications, vascular homeostasis is observed within a tight therapeutic range of 1,25(OH)2D treatment, however both vitamin D deficiency and overdose cause vascular damage (Figure 1.14) (Querfeld and Mak 2010).

1.8.6.1 Potential Toxic Effects

Vitamin D toxicity is a result of excessive number of ‘free’ 1,25(OH)2D, unbound to DBP, when there is already an excess of other vitamin D metabolites (Vieth 1990). In rats, 1,25(OH)2D hypercalcaemia is detected, only once the total of all vitamin metabolites exceed approximately 20% of the binding capacity of DBP (Shephard and Deluca 1980).

Previous studies using animal models confirm that the degree of toxicity is correlated to hypercalcaemia, type and concentration of vitamin D metabolite used.

Figure 1.14: Biphasic U curve representing vitamin D dosage (1,25(OH)2D3) in relation to cardiovascular complications in children with Chronic Kidney Disease (CKD). sHPT-secondary hyperparathyroidism. Adapted from: (Querfeld and Mak 2010).

For instance, studies on mice revealed that alfacalcidol is more toxic than 1,25(OH)2D, as high doses lead to nephrocalcinosis (Crocker et al. 1985).

Calcification following 1,25(OH)2D intoxication has been identified in the large

number of tissues, particularly kidney, aorta, lung, heart and subcutaneous tissue (Bills 1954, Jones 2008, Vieth 1990).

All, 1,25(OH)2D, 25(OH)D and 24,25(OH)2D increase levels of Ca-ATPase, enhance uptake of free calcium and increase cytosolic calcium levels in VSMCs, with 1,25(OH)2D being three times more potent than the other two metabolites (Inoue and Kawashima 1988, Kawashima 1988). This may explain toxicity of 1,25(OH)2D, supplementation – coupled with hampered calcium buffering in CKD it may

contribute to accumulation of calcium and phosphate product initiating the process of vascular calcification and influencing arterial tone. Oversuppresion of PTH with active vitamin D can lead to the development of adynamic bone disease (Brandenburg 2008). Also, decreased activity of 1-OHase mentioned earlier, is not the main obstacle in the treatment of patients with CKD. Another problem is the occurrence of 1,25(OH)2D resistance due to lower VDR numbers, accompanied by

toxic composition of uraemic serum interfering with 1,25(OH)2D-VDR binding to

DNA (Patel et al. 1995). Supplementation with higher doses 1,25(OH)2D in this

situation may result in hypercalcaemia, hyperphosphataemia, accumulation of high calcium-phosphate product, eventually leading to the development of VC and higher mortality risk.

Some however disagree - it has been postulated that if high levels of 25(OH)D can bind directly to VDR, this may also be triggering a response (Lou et al. 2004). In one of his papers DeLuca supports this notion by arguing that 1,25(OH)2D is not

responsible for toxicity, and that in fact toxicity is caused by vitamin D or 25(OH)D. The argument was supported by evidence that 1α-OHase null mice experienced identical toxicity to wild type and measurements confirmed that 1,25(OH)2D3 was

not synthesized in the -/- mice, excluding 1,25(OH)2D3 as a toxicant (Deluca H. F. et

al. 2010).