*4.5. Hexasodium Salt of Myo-Inositol Hexaphosphate*

A novel therapeutic option is the hexasodium salt of myo-inositol hexaphosphate SNF472, a potent calcification inhibitorin vitro [20]. SNF472 binds to the growth sites of hydroxyapatite crystals, the main constituent part of calcification deposits, thereby reducing the progression of ectopic calcification [20]. SNF472 inhibited CV calcification in adenine-induced CKD rats by up to 90% (Table 2) [20]. In ex vivo analysis using plasma from HD patients, hydroxyapatite crystallization potential was reduced by SNF472 [101,102]. The first phase 2 study CaLIPSO with 274 HD patients demonstrated attenuated progression of CAC and aortic valve calcification compared to placebo control, after 52 weeks of SNF472 treatment [21].

### **5. Promising Treatments of CV Calcification in Experimental CKD Models**

Opportunities for renal transplantation are low, and many patients su ffer from progressive CKD and its comorbidities. Existing drug therapies o ffer no adequate solution to treat/preven<sup>t</sup> CV calcification in CKD patients. In experimental non-transgenic CKD models, new promising therapeutic interventions and potential drug targets to decrease CKD-induced calcification and prevent or reverse pathophysiological complications have recently been shown. The isoflavonoid compound puerarin, found in the root of *Pueraria lobata*, has anti-inflammatory e ffects [103] and inhibited calcification in mouse vascular smooth muscle cells [76] and five-sixths nephrectomized rats (Table 5) [104].

PPARγ plays an important role in CVD and is closely connected to atherosclerosis [105,106]. Rosiglitazol, a PPARγ agonist, reduced vascular calcification in five-sixths nephrectomized mice (Table 5) [107]. Another potential drug target for CV calcification in CKD could be the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which is active in calcified vessels [108]. The NF-κB inhibitors tempol and triptolide reduced vascular calcification in an adenine-induced CKD mouse model [109], as well as in adenine-induced CKD rats (Table 5) [110]. Further, di fferent studies have shown that MR signaling can promote CV calcification [92]. Blockage of MR is increasingly applied as a therapy for improvement of CV outcomes in CKD, diabetes mellitus, hypertension, and heart failure. The MR antagonist spironolactone improved CV outcomes in patients with heart diseases [92] and inhibited dose-dependent vascular calcification and kidney damage in adenine-induced CKD rats (Table 5) [111].


**Table 5.** Potential therapeutic strategies that attenuate CV calcification in non-transgenic animal CKD models.

MR: mineralocorticoid.

### **6. Potential Diagnostic Tools for CV Calcification in CKD**
