Vascular ossification – calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis – calcific uremic arteriolopathy: the emerging role of sodium thiosulfate
© Hayden et al; licensee BioMed Central Ltd. 2005
Received: 03 February 2005
Accepted: 18 March 2005
Published: 18 March 2005
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.
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 poisioning and prevention of toxicities of cisplatin cancer therapies. It is used as a food and medicinal preservative and topically used as an antifungal medication.
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.
Keywordsatherosclerosis atheroscleropathy HDL-C lipoproteins osteoatheroitis oxidative and redox stress reactive oxygen species end stage renal disease
Atherosclerosis and vascular ossification – calcification (VOC) date to the time of the ancient Egyptians .
In the initial descriptive phase before the various hypotheses regarding the pathogenesis of atherosclerosis emerged, prominent pathologists of the time emphasized the bone like changes and used the terms ossification and petrification of atherosclerotic lesions.
Benivieni A. in 1507 and Fallopio G. (Fallopius) in 1575 were the first to record for posterity their initial descriptions of atherosclerosis. Fallopius, in 1575, described a degeneration of arteries into bone, which physicians of the time called ossification of the arteries . In 1863, Virchow labeled the vascular changes as "ossification, not mere calcification, occurring by the same mechanism by which an osteophyte forms calcium on the surface of bone" . During the 1800s a widely held concept was that VOC might be a protective mechanism to prevent aortic aneurysms from rupturing. In 1906, Bunting was able to demonstrate the presence of bone marrow containing its classical cellular contents including osteoclasts within a sclerotic aorta. He frequently debated the finding of ossification within the arterial vessel wall (AVW) and supported the finding that ossification was not a rare occurrence; rather it was just not specifically searched for at the time of autopsy .
VASCULAR OSSIFICATION – CALCIFICATION (VOC)
Tissue wound injury: a common link between two chronic diseases: OSTEOATHEROITIS and OSTEOARTHRITIS.
Tissue wound healing: a recapitulation of embryologic genetic memory
Injury – Inflammation: OSTEOATHEROITIS – OSTEOARTHRITIS
Granulation tissue formation (angiogenesis)
Endothelial cell activation, proliferation, migration: ANGIOGENESIS
Remodeling of the AVW: initially positive outward remodeling and over time a chronically negative inward arterial remodeling (see Scar contracture).
Resolution: results, only if the chronic injurious stimuli and sensitizers are removed from the endothelial, intimal, and medial layers of the arterial vessel wall.
The above 4 (R's): activate pleuripotent mesenchymal stem-cell pericytes and VSMCs to produce bone morphogenic proteins, which are also activated by (I): Injury and Inflammation with resulting inflammatory cytokines such as TNF alpha, IL-6 and decreased IL-10.
Scar: contracture and negative remodeling resulting in stenosis.
AVW stiffness even without ossification.
This orderly transformation of ossification has been demonstrated to occur in vitro by vascular mesenchymal cells, which undergo a transformation of monolayer growth to swirls, to ridges to a labyrinthine structure 
The vasa vasorum's guardian angel: the pericyte and its important role in VOC
Vasa vasorum: a custom delivery system
Supply the media and intima with vascular mesenchymal cells:
a. The multipotential, stem cell-like cell to contribute to the substrate of cells to produce an osteoid matrix by morphogenic bone proteins
b. A custom delivery system for Pi, Ca++, Glucose, Insulin, IGF-1, PTH, and other activators of bone formation
Substrates of the Renin Angiotensin Aldosterone System.
Substrates of native LDL-cholesterol and modified LDL-cholesterol.
Substrates of phospholipids from systemic circulating cells.
Substrates for angiogenesis. The endothelial progenitor cells, as well as, the endothelial cell and the pericyte itself via migration.
Supply the route for the "second wave" of inflammatory cells to the intima and vulnerable shoulder regions of the plaque, fueling the inflammatory process. The first wave originating from the endothelial luminal surface.
Supply the direct route for adventitial fibroblasts and TGF-beta allowing for intimal plaque expansion.
Bone siloprotein synthesized by the osteoblast-like VSMC has recently been shown to be an angiogenic protein capable of inducing neovascularization by interacting with the alpha v beta 3 integrin . Even more exciting is the finding that the endothelial pericyte is capable of synthesizing this non-collagenous angiogenic factor as well as being related to ossification of atherosclerotic plaques.
VOC IN metS AND T2DM
The multiple metabolic toxicities of the A-FLIGHT-U acronym
Multiple injurious stimuli responsible for the production of ROS.
Angiotensin II (also induces protein kinase C – β isoform)
Amylin (hyperamylinemia) islet amyloid polypeptide toxicity
AGEs/AFEs (advanced glycosylation/fructosylation endproducts)
Antioxidant reserve compromised
Absence of antioxidant network
ADMA (Asymmetrical DiMethyl Arginine)
Adipose toxicity: Obesity toxicity – Lipid Triad (decreased HDL-C, increased triglycerides and small dense LDL-C)
Adipocytokine toxicity: Increased TNF alpha, Il-6, TGF beta, PAI-I and the increased hormones resistin, leptin and decreased adiponectin.
Free fatty acid toxicity: Obesity toxicity – Lipid Triad
Lipotoxicity – Hyperlipidemia – Obesity toxicity – Lipid Triad
Insulin toxicity (endogenous hyperinsulinemia-hyperproinsulinemia)
IGF-1 – (GH-IGF-I axis) toxicity: This may serve to increase bone metabolism within the media of the AVW
Glucotoxicity (compounds peripheral insulin resistance) and induces reductive stress through the sorbitol/polyol pathway
Pseudohypoxia (increased NADH/NAD ratio)
Triglyceride toxicity: Obesity toxicity – Lipid Triad
Uric Acid – Xanthine Oxidase toxicity: Uric acid is an antioxidant early in physiological range of atherogenesis and a conditional prooxidant late when elevated through xanthine oxidase enzyme and generation of ROS: thus generating the paradoxical (antioxidant → prooxidant):
URATE REDOX SHUTTLE
Endothelial cell dysfunction with eNOS uncoupling, decreased eNO and increased
Hyperinsulinemia, Insulin-like growth factor-1 (IGF-1), and Amylin (IAPP)
Insulin, IGF-1, and amylin are known to be elevated in the insulin resistance (IR) and metS patient . Insulin has been long known be a growth factor and is a stimulus for hepatic synthesis of IGF-1, which may be implicated in the accelerated ossification in ASO. There is a human gene polymorphism with a phenotype described as the Benardinelle lipoatrophic syndrome more commonly referred to as lipoatrophic diabetes and this syndrome is associated with manifestations of acanthosis nigricans, generalized lipoatrophy, hirsutism, muscle hypertrophy, intellectual impairment, IR diabetes mellitus with major diet-dependent type V hypertriglyceridemia, and an increase in bone density, thus implying osteogenesis .
In addition to insulin and IGF-1, there is another beta cell derived islet hormone that is elevated in IR, metS, prediabetes, and early T2DM termed amylin or islet amyloid polypeptide. Amylin may be considered to be the fraternal twin of insulin and has recently been shown to be a physiologic regulator of bone remodeling through favoring bone formation, while inhibiting bone resorption and thus is osteogenic  (table 3).
Htn is the second leading cause of ESRD after diabetes. Hypertension plays an important role in the ASO associated with metS and T2DM, as atherosclerosis is non-existent in the pulmonary arterial tree and the venous system, due to a lower systemic intravascular pressure. Htn may be considered toxic to the AVW and is known to be associated with VOC (table 3) [19, 20, 24]. Mehrotra R and colleagues have recently demonstrated that hypertension plays a more putative role in the association of coronary artery calcification than do levels of serum calcium, phosphorus, parathyroid hormone, and 1,25 di-hydroxy vitamin D levels in T2DM patients not requiring dialysis 
Hyperlipidemia – Dyslipidemia and the Lipid Triad
The lipid triad of the metS and T2DM consists of an elevation in VLDL-C or triglycerides, small dense atherogenic LDL-C, and a decrease in HDL-C. Once these lipids become modified through oxidation in a milieu of increased ROS from the synergistic effect of the associated A-FLIGHT-U metabolic toxicities, they are a predictive determinate of osteogenesis within the media and intima of the AVW. The earliest changes associated of osteogenesis occur at the base of the lipid core in areas of necrotic-apoptotic macrophages and are associated with ROS and inflamation (figure 3). [1, 19, 20, 26, 27].
Hyperglycemia – Glucotoxicity: Impaired glucose tolerance (IGT) – impaired fasting glucose (IFG) – overt T2DM
Ishimura E et al have nicely demonstrated the importance of controlling HbA1c levels. They were able to demonstrate that for every 1 percent increase in HbA1c there was a 2.1 fold increase in the risk of VOC . Poor glycemic control seemed to be of greater importance than calcium and phosphate concentrations.
VOC in T2DM involves primarily the media of the AVW, however depending on the degree of underlying ASO; it may frequently involve the intima in those arteries where there is a more extensive involvement of atherosclerosis due to a deeper penetration of the adventitial Vv . Medial artery calcification has been shown to be a strong independent predictor of cardiovascular mortality in patients with newly diagnosed T2DM .
In a clinical longitudinal study of 4,553 Pima Indians the risk factors for medial artery calcification in T2DM were impaired vibration perception, long duration of diabetes, and high glucose concentrations as compared to non-diabetic matched controls, whose risk factors for VOC were age, male gender, and high serum cholesterol .
Serum uric acid (SUA) has long been known for its association with the metS and also it's role in T2DM has recently been discussed in length . SUA is an important substrate in the A-FLIGHT-U multiple metabolic toxicities and contributes to the production of ROS with resultant modification of lipoproteins as well as interfering with the normal function of the eNOS enzyme resulting in an uncoupling phenomenon discussed later (table 3).
Elevated SUA reflects the activity of the xanthine oxidase enzyme and its production of ROS, which subsequently has a positive effect on VOC. Tseng CH has been able to show that SUA is an independent risk factor for the development of peripheral arterial disease in T2DM .
Newer risk factors: Homocysteine (Hcy), inflammation (hs CRP), Microalbuminuria
Each of these novel risk factors plays a significant role in metS – T2DM and contributes to the calcification of the AVW through their association with the multiple metabolic toxicities and production of ROS while contributing to the inflammatory process (table 3).
Hcy is known to be toxic to the AVW resulting in a host of fibrotic remodeling changes as a result of autoxidation, VSMC activation, and proliferation, as well as the production of ROS . Li J. et al. have been recently able to demonstrate that Hcy potentiates calcification of cultured rat VSMCs .
Mediators of inflammation such as oxidation, carbonyl stress, C-reactive protein (CRP), and cytokines may directly stimulate vascular calcification. Also, inflammation reduces fetuin-A, a naturally occurring inhibitor of vascular calcification, which binds excess mineral in serum .
Increased levels of CRP are significantly associated with the presence of vascular calcification (including atheromatous and medial calcification) in both aorta and hand arteries, which may indicate a relationship between inflammation and vascular calcification in hemodialysis patients . It is of interest to note that IL-10 plays an important role as an anti-inflammatory cytokine and is known to be decreased in CKD and ESRD. Low monocyte IL-10 synthesis may contribute to a chronic inflammatory state in these patients by defective feedback inhibition of proinflammatory cytokine production . While inflammation plays a very important role, it is important to note that ROS occurs upstream from inflammation and that ROS are an important mediator of the nuclear factor kappa B [33, 34].
Microalbuminuria is recognized as a surrogate marker for systemic endothelial dysfunction . Recently, microalbuminuria has been shown to be a strong predicting factor of medial arterial calcification independent of nephropathy in patients with diabetes .
VOC IN CHRONIC KIDNEY DISEASE (CKD)
The RAAS Acronym: Redox Stress Reduction – Global risk reduction
Reductase inhibitors (HMG-CoA). Decreasing modified LDL-cholesterol, i.e., oxidized, acetylated LDL-cholesterol. Decreasing triglycerides and increasing HDL-cholesterol. Improving endothelial cell dysfunction. Restoring the abnormal Lipoprotein fractions. Thus, decreasing the redox and oxidative stress to the arterial vessel wall and myocardium.
AngII inhibition or receptor blockade:
ACEi-prils. ARBs-sartans. Both inhibiting the effect of angiotensin-II locally as well as systemically. Affecting hemodynamic stress through their antihypertensive effect as well as the deleterious effects of angiotensin II on cells at the local level – decreasing the stimulus for O2. production. The positive effects on microalbuminuia and delaying the progression to end stage renal disease. Plus the antioxidant effects within the arterial vessel wall and capillary. Antioxidant effects.
Aspirin antiplatelet, anti-inflammatory effect on the diabetic hyperactive platelet.
Adrenergic (non-selective blockade) in addition to its blockade of prorenin → renin conversion.
Non dihydropyridine calcium channel blocker – antagonists are preferred over dihydropyridine calcium channel blockers – antagonists in CKD.
Aggressive control of diabetes to HbA1c of less than 7. This usually requires combination therapy with the use of insulin secretagogues, insulin sensitizers (PPAR-gamma agonists), biguanides, alpha-glucosidase inhibitors, and ultimately exogenous insulin.
Decreasing modified LDL cholesterol, i.e., glycated-glycoxidated LDL cholesterol. Improving endothelial cell dysfunction. Also decreasing glucotoxicity and the oxidative-redox stress to the intima and pancreatic islet.
Aggressive control of blood pressure, which usually requires combination therapy.
Aggressive control of homocysteine with folic acid with its associated additional positive effect on re-coupling the eNOS enzyme reaction by restoring the activity of the BH4 cofactor to run the eNOS reaction via a folate shuttle mechanism and once again produce eNO.
Aggressive control of uric acid levels with xanthine oxidase inhibitors (allopurinol and oxypurinol) should be strongly considered in view of the prevailing literature in order to achieve more complete Global Risk Reduction
Aggressive control of hyperphosphatemia and elevated PTH and control intake of oral calcium while limiting vitamin D. Calcium carbonate should no longer be used as a phosphate binder in patients with calciphylaxis or patients at very high risk for developing calciphylaxis.
Statins. Improving plaque stability (pleiotropic effects) independent of cholesterol lowering. Improving endothelial cell dysfunction. Moreover, the indirect antioxidant anti-inflammatory effects within the islet and the arterial vessel wall promoting stabilization of the unstable, vulnerable islet and the arterial vessel wall.
Style. Lifestyle modification (weight loss, exercise, and change eating habits).
Statins: Emerging information: Positive effect on the Quality of HDL-C is emerging. i.e. prevents ox HDL-C and increases HDL-C 5–10 percent.
CVD accounts for the largest cause of death in ESRD patients and may range from 10 – 30 fold higher for those patients being treated with dialysis as compared to the general population . Patients entering dialysis over the past two decades now have a much higher incidence of diabetes and this is up to 59% as a first or second diagnosis with hypertension being the second leading cause of ESRD. Higher Framingham risk scoresand an aging population at the time of entry as a result of current technology and newer medications are preventing earlier coronary events and allowing them to survive and develop other end organ disease, such as ESRD and congestive heart failure, which are partly responsible for the increasing number of these patients .
Is atherosclerosis accelerated in this patient population or is there some other factor(s) related to the cardiovascular toxicity associated with uremia and dialysis?
Schwarz U et al. were able to demonstrate an increased size of the medial layer, marked increased calcification, increased number of calcified plaques, and a decreased lumen area in a study of 27 patients with ESRD compared to 27 non-renal disease controls that had died due to coronary atherosclerosis. Thus, there was no evidence to suggest an accelerated atherosclerosis, but instead, a major change in plaque composition with an increase in ossification and medial enlargement .
Proposed regulators of VOC
Minerals: Ca ++ Pi, Phosphate/Pit-1 → Cbfa-1
Bone morphogenic protein
Matrix gammacarboxyglutamate (Gla)-protein
Warfarin may also cause skin necrosis similar to CPLX via an impairment of Protein C with thrombosis in venules resulting in subcutaneous ischemia and Vitamin K – GLA inhibition.
Inflammation: TNFalpha, IL-6
Oxidized – retained – modified lipids (OxLDL-C, OxVLDL beta lipoproteins) and Low alpha lipoproteins: HDL-C
(may be a positive and negative regulator)
Elevated in human atherosclerosis and CVD yet paradoxically when you have a mouse model with knockout of OPG there is increased osteoporosis and VOC.
A-FLIGHT TOXICITIES (table 3)
Hormones: Insulin, IGF-1, Amylin, Leptin, and PTH
I or II Hyperparathyroidism
HYPOXIA activates hypoxia inducible factor Hif-1, ROS → Vascular angiogenesis
Multipotential → Pericyte
RANK and RANKL
These are involved but as with OPG the entire story is still evolving.
Scoble JE  presented the term atherosclerotic nephropathy in 1999, which includes abdominal atherosclerosis, renal artery atherosclerosis with renal artery stenosis, and atheroembolic disease. In older age populations, it has been estimated that atherosclerotic renal artery disease accounts for 14% (over the age of 50) and 25% of patients (over the age of 60) with end-stage renal failure [51, 52]. With the age groups over the age of 50 and 60 (baby boom – senior boom generation) expanding at an exponential rate in western countries we will see an increasing number of patients with ESRD attributable to this abnormality.
This atheroembolic phenomenon accounts for untold cases of ischemic nephropathy with functional loss of nephron units. Associated clinical companions of this condition that might alert the clinician would be: rapid increasing proteinuria, rapid deterioration of renal function, and other clinical evidence of peripheral atheroembolic phenomenon in other vascular beds such as the extremities in peripheral vascular disease (blue toe syndrome), mesenteric thrombosis and associated gastrointestinal bleeding, and extra cranial cerebrovascular atherosclerosis with associated transient ischemic episodes or overt cerebral thrombosis.
In atherosclerotic coronary artery disease we do not see evidence of intra-myocardial atherosclerosis and likewise, we do not find evidence of intrarenal atherosclerosis. The renal artery may be likened to an epicardial coronary artery when comparing these two diseases. It is currently accepted that atherosclerotic coronary artery disease and hypertension account for the major cause of death and congestive heart failure in developed countries. It is time to consider atherosclerotic renal artery disease with VOC and associated renal artery stenosis, as well as, hypertension as a significant cause of progressive CKD and its progression to ESRD.
As present in any atherosclerotic lesion, VOC is known to occur and will increase in the patient with CKD and ESRD (especially the patients with diabetes and ASO). VOC detected by non-invasive spiral CT scanning would alert the clinician to the possibility of renal artery stenosis and additionally alert the clinician to the importance for more aggressive therapeutic measures to control the A-FLIGHT-U toxicities (table 3) as well as to control the metabolic toxicities of the increased known sensitizers to VOC (table 5) (figure 6).
VOC IN CALCIPHYLAXIS (CPLX) – CALCIFIC UREMIC ARTERIOLOPATHY (CUA)
Any discussion of VOC would be incomplete without discussing the important issue of CPLX – CUA and a better understanding of this condition merits a janus-faced approach. The century old CPLX – CUA clinical syndrome, which once was considered to be a rare clinical phenomenon primarily associated with CKD and ESRD is now being reported and being seen in increasing numbers. Part of this increase may well be due to a better understanding and recognition of this syndrome and previous underreporting; however nephrology and dermatology departments, and dialysis clinics throughout the U.S. are seeing increasing numbers of this morbid – mortal complicated clinical syndrome. As the number of patients with CKD and ESRD continue to grow in numbers the medical community may well see this syndrome in near epidemic proportions (especially considering the current obesity – metS – T2DM epidemic).
CPLX is not unique to any one country and is a global phenomenon. As with any new and emerging clinical syndrome the literature is replete with multiple case reports of this entity. In this review, an attempt is made to increase the awareness and understanding of this malady and provide an overview and not reference the multiple rare and unusual case reports, unless they contribute to the understanding of mechanisms or treatment [53–63].
Historical perspective of CPLX
Selye's initial experiments in rats set the stage for the description of this clinical entity in humans . He hypothesized that sensitizers such as PTH or vitamin D might condition the vasculature to VOC. After providing the sensitization he then challenged the rats with known provoking factors including metal salts, albumin, and trauma, which induced calcium deposition and subsequent inflammatory necrosis of the skin and subcutaneous tissue. Over time other studies suggested alternate contributing factors, such as those listed in table 5. The name originated from the combination of calcium and anaphylaxis, thus calciphylaxis, however this model does not involve IgE mechanisms.
Byrant and White (1898) are credited as having described the first clinical presentation in a six-month-old infant, in which there was VOC and what they termed endarteritis obliterans, indicating involvement of the intima . It was not until 1969 that Rees and Coles used the terminology calciphylaxis to describe this clinical and pathologic syndrome in man .
Coates (1998) coined the term calcific uremic arteriolopathy (CUA) as a replacement term for CPLX, since in many instances elevations of Ca++, Pi or PTH levels are absent . Over time CUA may become the preferred term, as this newer terminology is only six years old. The term calciphylaxis is almost entrenched in the medical literature at this point in time; however Selye's animal model more closely parallels the dystrophic tumorous soft tissue calcifications of uremic CPLX. His model did not exhibit the histology consistently described with uremic CPLX, i.e. small vessel calcifications and intimal hypertrophy in association with panniculitis (lobular fat necrosis, and inflammatory changes with neurtrophils, lymphocytes and macrophages, and small vessel thrombosis or involve IgE mechanisms [54, 67–69]. We favor the term: obliterative calcific vasculopathy.
The skin in CPLX
The skin lesions of CPLX present as painful violacous (livedo reticularis) areas in the extremities, proximal medial thighs, anterior abdomen and lateral flank areas, the breast in females, and frequently overlie or are adjacent to subcutaneous tumorous calcifications in areas of increased adipose tissue. They then progress to a blackened eschar, which later reveals itself on a granulating bed and enlarges at the periphery of the ulcer. They have a tendency to develop in sites of prior skin trauma, such as abdominal scars from previous surgical incisions and may even develop from the trauma of simple scratching of extremities due to ESRD-associated pruritis.
It is important to recognize the clinical presentation of the skin color changes and the neuropathic type of pain before ulceration has developed. If we wait until skin ulceration develops we place the CPLX patient at an increased risk of sepsis and premature death. We should carefully assess any palpable calcific tumorous masses in the subcutaneous tissue in patients at high risk for CPLX.
Differential diagnosis of cutaneous ulcers
Peripheral arterial disease
Necrotizing vasculitis – Collagen vascular diseases -
Infectious endocarditis with septic emboli
CALCIPHYLAXIS (CPLX) – CALCIFIC UREMIC ARTERIOLOPATY (CUA)
Diabetes: (T1DM – T2DM)
Peripheral vascular disease accelerated atherosclerosis (atheroscleropathy) ASO Insulin injection sites (sharp trauma)
Necrobiosis lipoidica diabeticorum?
Sharp – Blunt – pressure ulcers at pressure points due to immobilization
Thermal (Hot or Cold [cryoglobulinaemia]) – Radiation
Brown Recluse spider bite
Collagen Vascular Diseases – Necrotizing vasculitis specifically SLE, systemic sclerosis (Scleroderma)
Pyoderma gangrenosum usually associated with chronic inflammatory diseases such as: ulcerative colitis, Crohn's disease, and rheumatoid arthritis
The recent emergence of a newer skin pathology termed: neprogenic fibrosing dermopathy may appear co-morbidly with CPLX and recently it has been reported that transforming growth factor beta-1 (TGF beta-1) may to be related to both disorders . By making an accurate and earlier diagnosis of CPLX, a greater effort may be given by the primary care provider and the nephrology team as well as other specialties (dermatology and plastic surgery) to improve the multiple A-FLIGHT-U toxicities in each patient (table 3). Earlier treatment of each altered abnormality of the associated multiple metabolic derangements may prevent or delay the progression of this morbid mortal clinical syndrome (table 4,5).
Endotheliopathy, redox stress, and reactive oxygen species. eNOS and eNO
The positive effects of eNOS and eNO
• Promotes vasodilatation of vascular smooth muscle.
• Counteracts smooth muscle cell proliferation.
• Decreases platelet adhesiveness.
• Decreases adhesiveness of the endothelial layer to monocytic WBCs (the "teflon effect").
• Anti-inflammatory effect.
• Anti-oxidant effect. It scavenges reactive oxygen species locally, and acts as a chain-breaking antioxidant to scavenge ROS.
• Anti-fibrotic effect. When NO is normal or elevated, matrix metalloproteinases (MMPs) are quiescent; conversely if NO is low, MMPs are elevated and active. MMPs are redox sensitive.
• NO inhibits prooxidant actions of uric acid during copper-mediated LDL oxidation.
• NO has diverse anti-atherosclerotic actions on the arterial vessel wall including antioxidant effects by direct scavenging of ROS – reactive nitrogen species RNS.
The endothelial cell is important in controlling the function of small arterioles and how they may become a net producer of ROS. This endothelial dysfunction may precede the vascular narrowing – closure, prothrombotic state, thrombosis with resulting ischemia of the surrounding subcapillary interstitium, ischemic necrosis of the subcutaneous adipose tissue, and skin changes of livedo reticularis with transformation to painful necrosis, eschar formation, and skin ulceration.
In addition to correcting the underlying multiple metabolic A-FLIGHT toxicities and positive regulators of VOC (table 3,5), a strong consideration to newer therapies should be entertained in order to prevent, slow, and alter the morbid – mortal natural history of the dreaded complications associated with CPLX – CUA.
Sodium thioSulfate (STS) intravenous therapy for calciphylaxis: its emerging role
STS is known to be a chelator of cations and has been used for over a century as an antidote for cyanide toxicity, topical treatments of acne and versicolor, and recently as a chemoprotectant against carboplatin and cisplatin toxicity. Its use in the treatment of calciphylaxis has only recently been described and its future use may become a standard of care in the treatment of the dreaded complications . Its dual role as an antioxidant and chelator makes STS an excellent choice for the treatment of calciphylaxis and it will be interesting to follow future clinical trials regarding it use.
Clinically, STS seems to have a rather intriguing rapid response in the relief of the pain associated with CLPX and it frequently reduces pain within the very first few treatments (personal experience). Additionally, it seems to promote healing of skin ulcerations especially when used in conjunction with hyperbaeric oxygen treatments .
The STS hypothesis
STS may restore endothelial cell dysfunction in CPLX through its antioxidant actions and have a positive effect on eNOS uncoupling and eNO generation. We have formed a hypothesis that the rapid reduction in pain may be due to a restoration of endothelial dysfunction associated with this syndrome. The anitoxidant effect of STS, given in the intravenous dosage of 12.5–25 grams intravenous at the end of dialysis may help to restore the dysfunctional endothelial cell and begin restoring the endothelium's natural tendency (in health) to produce eNO (promoting vasodilation) instead of the dysfunctional super oxide and the resultant peroxynitrite (promoting vasoconstriction) (figure 8) [1, 19, 20, 27, 28, 34, 45].
Diabetic and peripheral arterial disease patients may be slower to respond as they are plagued with a much more intense endothelial cell dysfunction and endothelial nitric oxide enzyme uncoupling due to the advanced atherosclerotic process and medial calcifications and associated ischemic changes.
Undoubtedly the essential cofactor tetrahydrobiopterin (BH4) becomes depleted during this chronic ischemia in the subcutaneous tissue from the multiple metabolic toxicities. STS may have a "folate-like redox shuttle effect" similar to the pleiotropic effects of folic acid supplementation  by allowing the oxidized cofactor BH3 and BH2 to undergo a restoration by the antioxidant effects of STS to the requisite completely reduced form BH4. This may ameliorate the underlying oxidative stress within the pre-capillary and capillary beds of the interstitium and the endoneurium of the peripheral neuronal units involved. While this is only a hypothesis it seems to be clinically relevant due to the clinical observation of a rapid relief of the pain associated with CPLX.
Emerging role of nanobacteria
Currently, the multiple roles of nanotechnology and nanobacteria are rapidly emerging and with new findings come new ideas, which may have a significant impact regarding the future of medicine. Nanobacteria may be a causative agent of diseases related to the biomineralization processes. As clinicians and scientists we must be careful as newer hypothesis and treatments emerge. For example even though nanobacteria have been found in multiple disease states associated with calcium deposition, we have yet to fulfill Koch's postulates regarding VOC. Because this information has just evolved it is important to review some of the background in this field of study.
We have witnessed the exciting story of H. pylori and its causative role in ulcer disease and followed the C. pneumonia story in atherosclerosis finding it to be one of the burdensome infectious injurious stimuli to the endothelium that results in remodeling and atheromatous changes in the AVW. Likewise, the new information regarding nanobacteria being associated with VOC is exciting and could play a very important role in the causation of the atheromatous process and VOC (figure 2).
Nanobacteria belong to the family of gram-negative rods (approximately 100 fold smaller in size) and have been recently localized in cardiovascular tissue. Miller VM et al. have found nanometer-scale particles (ranging in size from 30 to 100 nm) similar to those described as nanobacteria isolated from geological specimens and human kidney stones. These ultra small microbes can be visualized in and stained immunohistologically from calcified human cardiovascular tissue . Jelic et al. have demonstrated the presence of nanobacteria in a mitral valve associated with a localized calciphylaxis within mitral vegetations from a patient with T2DM .
Maniscalco BS et al., have been able to demonstrate a statistically significant improvement in coronary calcium scores (inferring a reversal of VOC) and a reduction in angina in a group of patients with CAD and coronary artery calcifications using thecombination of EDTA by rectal suppository and a combination of multiple known antioxidants with 500 mg tetracycline (nanobacteriocidal) given daily by mouth. The treatment duration was 4 months .
Recently the literature has been replete with the association of periodontal disease and its relation to cardiovascular disease and events. Whether this condition is responsible for the activation of the chronic inflammatory disease response driving the atherosclerotic process or not remains to be seen. The recent isolation of nanobacterium with periodontal disease has fueled the fire of this being a putative microorganism in the development and progression of atherosclerotic disease and VOC .
Osteoporosis and VOC
The coexistence of osteoporosis, CVD, and VOC with the aging process in humans and the concept of a shift of calcium from the osseous skeleton towards the AVW have been suggested as one of the explanations for their simultaneous existence [76, 77].
Accumulating evidence indicates that there are similar pathophysiological mechanisms underlying both diseases. The A-FLIGHT-U multiple metabolic toxicities and resultant ROS, oxidative stress, endothelial cell dysfunction, endotheliopathy, and inflammation have been central issues in this paper regarding VOC. Each of these is associated with a modulation of vascular and osteogenic cells but in an opposite manner and may act in a synergistic manner. The finding of oxidative stress promoting VOC while promoting osteoporosis may help to explain the paradoxical parallel buildup of VOC and the concurrent loss of bone mineralization in the osseous skeleton [78–80]. The current evidence linking both of these diseases is far from conclusive and additional research is necessary to further characterize the relationship between these two common illnesses as our population of baby (senior) boomers are aging in large numbers.
One such exciting and current emerging area in vascular biology involves the RANKL/RANK/OPG system, which belong to the tumor necrosis factor-related family recently discovered to be critical regulators of the immune system and skeletal biology. RANK(L) (receptor activator of nuclear factor kappaB (ligand) may promote and osteoprotegerin (OPG) may protect against vascular calcification (table 5). The mouse OPG knockout model displays osteroporosis and increased vascular calcification and human gene polymorphisms of OPG are currently being defined and how they may confer an increased risk of CAD in Caucasian men while interacting with VOC and osteoporosis . The finding that OPG levels may reflect endothelial cell dysfunction is certainly an area under serious consideration [76, 82].
CPLX and T2DM
The diabetic patient is already plagued with an underlying accelerated atherosclerosis (atheroscleropathy (ASO)), as well as, medial fibrosis and VOC (even if they do not develop CKD or ESRD requiring dialysis). With the current epidemic of obesity, metS, insulin resistance related T2DM (diabesity) in all age groups and particularly the aged and adolescent youth, a closer examination of this morbid – mortal complication is in order [83–87].
If these T2DM patients do develop CKD and/or ESRD requiring dialysis they could be at a much higher risk of developing an even more severe form of VOC. This dual effect of having not only T2DM related medial calcification but also having the increased risk for the development of medial remodeling and VOC from CKD and/or ESRD requiring dialysis would place these individuals at an extremely high risk for the development of excessive medial arterial remodeling and VOC, as well as arteriole remodeling and VOC, which could possibly increase the risk of developing CPLX (figure 2, 7). Many T2DM patients may have medial arteriolar calcification that could be contributing to anunderlying skin necrosis currently being attributed singularly to peripheral arterial disease and ischemic necrosis or gangrene, when if fact they might have coexisting arteriolar calcification contributing to their skin changes of gangrene. This dual mechanism of VOC in the arterioles and conduit arteries could be playing an important role in development of CPLX.
The treatments to date have largely consisted of careful wound management, hyperbaric oxygen therapy , and specific treatment of wound infections, which frequently become systemic and result in deadly sepsis, organ failure, and patient demise. These open ulcerations of the skin are extremely difficult to heal and while they remain open they place the patient at an extreme risk of infection, as this patient population is known to have an impaired immune system from the combination of dialysis and T2DM . If STS does emerge as a treatment option for those with CPLX then a careful evaluation of the T2DM patient with skin ulceration should be explored and consideration given to the use of STS provided there is evidence of an associated arteriolar calcification in addition too medial calcification of the conduit arteries. The dual effect of STS being an antioxidant and a chelator of calcium could have a positive outcome in promoting healing of skin ulcerations, thus reducing the possibility of systemic infection and furthermore result in limb salvage of these high risk patients who seem to be presenting to dialysis clinics more and more as the obesity – T2DM epidemic continues to progress. Additionally, the use of STS may be considered in the treatment of VOC associated with CHD and peripheral arterial disease independent of CKD and dialysis.
This review has been an attempt to increase our basic understanding of VOC and its mechanisms in the patient with metS, T2DM, CKD, CHD, and the syndrome of CPLX. By improving our understanding of the mechanisms in play we may be better equipped to prevent many of the complications associated with VOC.
VOC is an exciting and complicated field of study and while our understanding of this process has undergone considerable improvement regarding its mechanisms and understanding during the past few years, there remain many questions to be solved and newer therapies proposed to help decrease the morbid – mortal complications of this actively regulated process.
The recent publications of case reports regarding the use of STS to treat the complications of VOC and the syndrome of CPLX may result in the necessary clinical trials and the important scientific animal experiments to fully evaluate and understand its effect. Additionally these early published clinical results should instigate the necessary studies to better understand the mechanisms of this emerging treatment for calciphylaxis and its possible role in treating VOC in patients with CHD, atherosclerosis and atheroscleropathy in metS, and T2DM. Additionally, this emerging treatment may have significant applications for diabetic patients with CKD, ESRD. and VOC.
Earlier diagnosis of the patient at risk for the development of VOC is important so that a global risk reduction program can be initiated in order to control for the multiple metabolic toxicities by applying the therapeutic RAAS acronym (table 4) for the treatment and prevention of complications . While this remains a daunting task for clinicians it can be undertaken by a team effort approach involving our multiple resources and sub-specialties in medicine.
List Of Abbreviations
arterial vessel wall
coronary heart disease
chronic kidney disease
calcific uremic arteriolopathy
endothelial nitric oxide
endothelial nitric oxide synthase
end stage renal disease
high density lipoprotein cholesterol
highly sensitive C-reactive protein
insulin like growth factor-1
interleukin 6 and 10
low density lipoprotein cholesterol
Matrix gammacarboxyglutamate (Gla)-protein
nuclear factor kappa B
receptor activator of nuclear factor kappaB
receptor activator of nuclear factor kappaB ligand
reactive oxygen species
serum uric acid
- T1DM T2DM:
type (1) (2) diabetes mellitus
very low density lipoprotein cholesterol
vascular ossification – calcification
vascular smooth muscle cell
The authors would like to acknowledge the brave heroes who live to be dialyzed and undergo dialysis to live. Additionally, we acknowledge all the brave scientists and clinicians who have made renal replacement possible for these people requiring treatment for ESRD. We also wish to acknowledge The National Institutes of Health, The National Kidney Foundation, and The National Institute of Diabetes, Digestive, and Kidney Diseases for their generous time and grants, which make this type of research possible for the public at large. We wish to thank those who have been organ donors.
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