Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate

Abstract

Background: Vascular calcification is associated with metabolic syndrome, diabetes, hypertension, atherosclerosis, chronic kidney disease, and end stage renal disease. Each of the above contributes to an accelerated and premature demise primarily due to cardiovascular disease. The above conditions are associated with multiple metabolic toxicities resulting in an increase in reactive oxygen species to the arterial vessel wall, which results in a response to injury wound healing (remodeling). The endothelium seems to be at the very center of these disease processes, acting as the first line of defense against these multiple metabolic toxicities and the first to encounter their damaging effects to the arterial vessel wall.

Results: The pathobiomolecular mechanisms of vascular calcification are presented in order to provide the clinician-researcher a database of knowledge to assist in the clinical management of these high-risk patients and examine newer therapies. Calciphylaxis is associated with medial arteriolar vascular calcification and results in ischemic subcutaneous necrosis with vulnerable skin ulcerations and high mortality. Recently, this clinical syndrome (once thought to be rare) is presenting with increasing frequency. Consequently, newer therapeutic modalities need to be explored. Intravenous sodium thiosulfate is currently used as an antidote for the treatment of cyanide poisoning and prevention of toxicities of cisplatin cancer therapies. It is used as a food and medicinal preservative and topically used as an antifungal medication.

Conclusion: A discussion of sodium thiosulfate's dual role as a potent antioxidant and chelator of calcium is presented in order to better understand its role as an emerging novel therapy for the clinical syndrome of calciphylaxis and its complications.

Figure 1

Coronary artery calcification. This image demonstrates coronary artery calcification. This 68 year-old Caucasian male with CAD, congestive heart failure and angina was found at autopsy to have a complete occlusion of the LAD with thrombus. Known T2DM of 8 years duration and Htn of 10 years duration with normal CA⁺⁺ and Pi, BUN 32 mg/dL, creatinine 1.8 mg/dL, proteinuria trace to +1, total cholesterol 198 mg/dL, and triglycerides 398 mg/dL

Figure 2

The central role of the endothelium in VOC and atherosclerosis. This image portrays the endothelium as the first line of defense against multiple injurious stimuli. Most of the injurious stimuli are represented by the A-FLIGHT-U toxicities found in table 3. When discussing the role of VOC and how it ties into atherosclerosis and the accelerated ASO associated with metS, prediabetes, and overt T2DM it is important to include the various interactions of A-FLIGHT-U toxicities with the associated ROS and the sensitizers for calcium deposition and ossification (Ca⁺⁺, Pi, PTH) within the AVW (both the media and intima) in table 5. The role of ROS, inflammation monocyte-macrophage foam cells undergoing apoptosis – necrosis with creation of a nidus and the stimuli for the VSMC and pericyte following the neovascularization (Vv) of the media and intima to result in osteoid formation and later the mineralization within these atherosclerotic plaques. This image also portrays the possible role for nanobacteria in addition to C. pneumonia as well as other bacteria and viral infections as possible contributing factors for the ossification process.

Figure 3

Matrix vesicle formation at the base of the lipid core. This image depicts the formation of matrix vesicles at the base of the lipid core in an atherosclerotic plaque. These vesicles are generated through the wound healing process and act as a nidus for later plaque ossification. A 32 year-old male smoker killed in a motorcycle accident. Left anterior descending coronary artery. Note the basophilic staining at the base of the lipid core (starred) and surrounding areas. This area represents early changes of atheromatous ossification. Coronary artery calcification may not be detected until later in life, however this image portrays VOC as being an active directed process beginning early in life.

Figure 4

Transitional stages in VOC. Transitional stages in vascular calcification recapitulate embryonic endochondral ossification, including an acellular matrix (matrix), amorphous mineralized matrix (calcified matrix), remodeling (osteoid), and following neovascularization of adventitial Vv vessels, complete bone tissue (bone mineralization).

Figure 5

The multipotential, pluripotent (stem cell – like), and mesenchymal pericyte. The pericyte is considered to be a differentiated VSMC, which acts as guardian angel of the endothelial cell. It is capable of synthesizing most of the non-collagenous bone morphogenic proteins associated with VOC.

Figure 6

Sensitizers and the Cbfa-1 "protein switch" to transform mesenchymal cells into osteroblast-like cells. This slide demonstrates the transformation of the pluripotent mesenchymal VSMC and pericyte into an osteoblast-like cell. It reveals the importance of the ossification sensitizers and core binding factor alpha-1 Cbfa-1 emphasizing their important role in VOC.

Figure 7

Histologic changes in a patient with CPLX and ESRD. Breast biopsy (benign) from a non-diabetic 60-year-old Caucasian female with an irregular breast mass 12 months prior to the development of clinical abdominal CPLX (multiple tumorous calcifications in the abdominal adipose tissue and skin ulceration). These tissue sections demonstrate the underlying systemic VOC of calciphylaxis. Her ulcerated area on the abdomen was not biopsied due to a possibility of aggravating tissue healing. Panel a: Demonstrates the H&E basophilic staining of intimal VOC in a small musculoelastic artery. Panel b: Demonstrates the medial fluorescent-like staining (due to inverted coloration of H & E basophilic staining) of VOC in an arteriole. Note the adjacent venule medial VOC staining. Venular VOC – thrombosis has not been as extensively studied as the arteriole and one must consider the possibility that VOC – thrombosis in the post-capillary venule may be important as the increased capillary edema and pressure may result in capillary endothelial dysfunction and promote an additive factor in the important role of subcutaneous ischemia and skin necrosis and ulceration. Note the panarteriolar involvement of the intima, media, and adventitia in the various vessels. Panel c: Demonstrates the H & E basophilic adventitial staining of VOC in an arteriole.

Figure 8

Uncoupling of the eNOS enzyme resulting in the net production of superoxide instead of the protective endothelial nitric oxide (eNO). This image depicts the eNOS enzyme reaction and resultant production of the protective antioxidant, anti-inflammatory gas product eNO. Oxygen reacts with the eNOS enzyme in which the tetrahydrobiopertin (BH₄) cofactor has coupled nicotinamide dinucleotide phosphate reduced (NAD(P)H) enzyme with L-arginine to be converted to nitric oxide (NO) and L-citrulline. When eNOS uncoupling occurs the NAD(P)H enzyme reacts with O₂ and the endothelial cell becomes a net producer of superoxide (O₂^•) instead of the protective endothelial NO. This figure demonstrates the additional redox stress placed upon the arterial vessel wall and capillaries in patients with MS, PD, and overt T2DM.

Figure 9

Sodium thiosulfate. This figure demonstrates the chemical structure of sodium thiosulfate, which is an antibrowning, reducing, and antioxidant agent: Capable of donating electrons to re-pair unpaired damaging electrons to be an effective antioxidant as well as a chelator of cations such as the calcium excess in calcific uremic arteriolopathy – CPLX.

Figure 10

Neuronal calciphylaxis. This image demonstrates not only medial calcification of an arteriole but also calcification of the epineurium of a peripheral neuronal unit within the subcutaneous tissue of a patient with systemic CPLX. This is from the same patient and breast biopsy tissue as in figure 7. Calcium stains black in this von Kossa stain.