Clinical criteria for definition of scleroderma renal crisis [1].
\r\n\tThe automotive sector is transforming its fleet of vehicles to adapt them to this requirement of society, which is also being translated into increasingly restrictive legislation.
\r\n\tOther alternative fuels are currently considered in the deployment of a new mobile fleet that will entail a change in the way we move - sharing resources, such as the vehicle - and the resources and way of refueling.
\r\n\tAnd this transformation takes us further and further away from the oil sector as the only fuel for mobility. It is already common to consider a fraction of biodiesel or bioethanol in current fossil fuels, but the policy is moving towards a greater penetration of renewable energy resources.
\r\n\tMost of the new renewable sources will be generated in a distributed scenario, so it is necessary to study the logistic to transport them in a cost-effective and sustainable way.
\r\n\tIn summary, the aim of the book encompases the whole cycle of the energy resources, both conventional and renewables, associated to mobility.
Systemic sclerosis (SSc) leads to morbidity and mortality through a combination of inflammation, fibrosis, and vascular damage leading to internal organ complications affecting the heart, lung, bowel, and kidneys. In SSc, we observe kidney involvement as three main clinical situations described below.
\nMost often, SSc causes a range of renal manifestations, which occur in both subsets of the disease: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets.
\nAs overlaps are often seen in connective tissue diseases, SSc should be associated with other immunological features of renal disease findings typical for systemic lupus erythematosus (as lupus glomerulonephritis) and ANCA-associated vasculitis/glomerulonephritis.
\nScleroderma renal crisis (SRC) is a dramatic and classical scleroderma manifestation, historically known as dominant cause of scleroderma-related death. Currently, the leading causes of death in scleroderma are pulmonary fibrosis and pulmonary arterial hypertension [1]. Regardless, one-year SRC outcomes remain poor, with over 30% mortality and 25% of patients remaining dialysis-dependent.
\nTo make the summary complete, possible drug-related adverse events including from toxic renal involvement to renal acute renal failure must be mentioned.
\nSRC occurs usually in early dcSSc (11%), as compared to patients with lcSSc (4%) [2, 3]. SRC is more common in rapidly progressing disease, SRC was previously reported up to 25% of SSc, but over time, it was found that incidence of renal crisis appeared to have decreased since improvement of early diagnostics [1].
\nHistorically, study of Steen and Medsger [4] presented change of mortality causes during 1972–2002 years. This study showed that SRC as the cause decreased from 42 to 6% of SSc-related deaths, while the proportion of other causes of death increased: pulmonary fibrosis rose from 6 to 33% and pulmonary arterial hypertension from 22 to 28%. Large data were obtained prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort. The EUSTAR database was inaugurated in June 2004 and represents a multinational, prospective, and open SSc cohort [5]. According to EUSTAR data, SSc-related deaths include pulmonary fibrosis 19%, pulmonary arterial hypertension 14%, arrhythmia 6%, heart failure 7%, and SRC 4%. Non–SSc-related deaths in total 4% include infection 13%, malignancy 13%, and cardiovascular 12%. Renal causes accounted for the death of 10 patients (4%), all due to renal crisis. Renal crisis was fatal in 16% of all patients experiencing renal crisis [5].
\nPathogenesis is characterized by series of insults (Figure 1):
Changes in intima and endothelium: Initially, there is injury to the endothelial cells with intimal thickening and proliferation in the arcuate and interlobular arteries [6].
Absence of inflammation: There is a notable absence of inflammatory cells (lymphocytes and monocytes) in the renal vasculature [6].
Vascular injury: Platelet factors are released causing increased vascular permeability, fibrin deposition, and collagen formation, which lead to further luminal narrowing [6].
Renal ischemia: Narrowed renal arterioles decrease renal cortical blood flow [6].
Activation of renin: Renal ischemia and episodic renal vasospasm “renal Raynaud phenomenon” contribute to decrease of blood flow. Decreased renal blood flow causes hyperplasia of the juxtaglomerular apparatus and release of renin [6].
Secondary small vessel changes: endothelial injury is associated with thrombus formation. Intravascular thrombi and mucoid intimal edema may be seen in renal histology. Small vessel thrombi are more abundant than glomerular thrombi (unlike the pathology seen in hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura) [7].
The mechanisms in the pathogenesis of SRC. Adapted from Steen et al. [8].
Histopathological findings of SRC are more frequently manifested by severe involvement of small arteries and arterioles. Early vascular changes are characterized by intimal accumulation of myxoid material in the interlobular and arcuate arteries, which results in severe luminal narrowing (Figure 2). Sometimes microthrombi are developed in the affected vessels and fragmented red blood cells can be seen in vessel wall. Microthrombi in arterioles can also progress to the glomeruli. When the arterioles incoming to glomeruli are predominantly affected, the morphological features in glomeruli are characterized by ischemia with wrinkling of glomerular basement membrane and ischemic collapses of glomeruli (Figure 3). When microthrombi are developed mainly in outgoing arterioles, the corresponding pathology is severe congestion and hemorrhagic necrosis of the tufts (Figure 4).
\nEarly vascular changes are characterized by intimal accumulation of pale myxoid material in the small artery, which results in severe luminal narrowing (Methenamine-silver stain).
Two types of glomerular injury associated with scleroderma renal crisis. Ischemic collapse of glomerulus with wrinkling of glomerular basement membrane corresponds to arterial stenosis.
Two types of glomerular injury associated with scleroderma renal crisis. Thrombotic microangiopathy with occlusion of outgoing arteriole is characterized by the congestion and hemorrhagic necrosis of the tuft (Methenamine-silver stain).
Later arterial injury is characterized by change of edematous mucoid intima to the concentric lamination and so called onion skin lesion (Figure 5) with significant luminal reduction. In glomeruli, the lesion is represented by double contouring of glomerular basement membrane (as a result of prolonged or repeated endothelial injury) and segmental or global sclerotic lesions.
\nProminent intimal concentric lamination within an interlobular artery (arterial onion skin lesion) with irreversible reduction of the arterial lumen (Methenamine-silver stain).
Because blood supply in the kidney is represented by end vessels without collaterals, each area of kidney tissue after arterial luminal narrowing must suffer from severe ischemia or even tissue necrosis. In histopathology, pronounced ischemia leads to tubular injury in the intersticium and tubular atrophy with interstitial fibrosis in the course of time.
\nSince none of these findings are specific for SRC, the pathological diagnosis must be supported by appropriate clinical and serological data [9].
\nHistopathology: with courtesy of Eva Honsová, MD., PhD. Department of Pathology IKEM, Prague.
\nSRC is defined as new onset of accelerated arterial hypertension and rapidly progressive oliguric renal failure during the course of SSc. There are differences between the criteria used to define SRC [1]. Occasionally, more modest elevations in blood pressure and renal dysfunction and at times normotensive presentations were found [9, 10]. The diagnosis is complicated in the case of malignant hypertension with absence of kidney impairment.
\nSRC was defined in a minority of studies and criteria were heterogeneous [10]. It is a problem to establish criteria for SRC, because the clinical spectrum of SRC is broad, ranging from accelerated hypertension to normotensive patients 7% [10]. Arterial hypertension is a typical symptom in SRC accompanied by classical complications such as hypertensive encephalopathy, retinopathy, congestive heart failure, hemolysis, etc. Diagnosis of SRC in patients without pre-existing SSc diagnosis and in normotensive SRC patients is difficult, mainly in the absence of renal biopsy [10, 11].
\nOnly one study up to now has partially validated criteria for SRC (Table 1) [8]. It was proposed by experts in 2003. It included items for systolic and diastolic blood pressure, serum creatinine, proteinuria, hematuria, microangiopathic hemolytic anemia, and renal histopathology. These are known as the Ancona criteria for SRC [8].
\nSRC is defined as following, requiring both: | \n
A new onset of blood pressure >150/85 mm Hg obtained at least twice over a consecutive 24-hour period. This blood pressure is chosen because it is defined by the New York Heart Association as significant hypertension. | \n
Decrease in the renal function as defined by a decrement of at least 10% in the estimated GFR (eGFR) or GFR of <90 (mL/min/1.73 m2. When possible, a repeat serum creatinine and recalculation of the GFR should be obtained to corroborate the initial results. | \n
In order to corroborate further the occurrence of acute renal crisis, it would be desirable to have any of the following, if available: | \n
\n
| \n
Notes \n
| \n
Clinical criteria for definition of scleroderma renal crisis [1].
SRC, scleroderma renal crisis; GFR, glomerular filtration rate.
Recently, the Scleroderma Clinical Trials Consortium (SCTC) and Scleroderma Renal Crisis Working Group generate a core set of items to develop classification criteria for SRC using Delphi methodology. The final core set of items to develop classification criteria for SRC contains domains: blood pressure arise, kidney impairment, hematological changes, thrombotic microangiopathy, and organ dysfunction. A consensus definition of SRC is urgently needed to standardize data collection on SRC [9].
\nNovel concepts of SRC classification included the stratification of SRC:
definite SRC: defined as at least two of: new onset hypertension, microangiopathic hemolytic anemia (MAHA), and rising creatinine
subacute forms of SRC: such as hypertension, renal insufficiency, and renal sediment changes in the absence of microangiopathic hemolytic anemia [9, 10]
New concept also includes the addition of ACE inhibitor responsiveness as a characteristic of hypertension (in probable SRC) and the addition of more specific time frames for measurement of blood pressure (taken twice, 2 hours apart, within 3 days of first event-associated observation) [10].
\nIn addition to heterogeneity and rarity, the absence of a gold standard and classification criteria are important challenges for research on SRC. The development of new criteria is important to improve the definition of normotensive SRC. In this case, performing kidney biopsy and examination of biomarkers (including anti-RNA III polymerase) are important and promising.
\nKidney biopsy is not mandatory for diagnosis of SRC. In patients at risk of SRC with its typical clinical presentation, kidney biopsy is usually not performed. However, it should be considered in all patients with atypical presentation and findings, especially in normotensive patients, patients with ANCA positivity, severe proteinuria, and nephrotic syndrome.
\nIn most patients, we cannot perform kidney biopsy immediately as severe hypertension and frequently present thrombocytopenia significantly increase the risk of bleeding. Biopsy is usually performed within a few days after blood pressure correction and is done with reasonably low risk in patients with blood pressure below 160/90 mmHg and thrombocyte count above 100 × 109/l.
\nIdentification of SRC predictive factors (before the development of SRC) is essential (Table 2). The vast majority of SRC cases (75–80%) occur in patients with diffuse skin involvement, i.e., skin scleroderma proximal to knee and elbow (dcSSc patients), and rapid progression of skin thickening has been shown to be associated with the development of SRC [12]. Arthritis, palpable tendon friction rubs, swollen fingers, and distal parts of hands are routine syndrome in patients with early dcSSc [13]. Tendon friction rubs were confirmed to be an independent predictor of SRC (HR: 2.33) [14].
\nSRC patient-specific characteristics | \n
Race—black Gender—male sex | \n
SSc characteristics | \n
Short course of SSc Diffuse cutaneous systemic scleroderma Modified Rodnan skin score (>14 or 20) Musculoskeletal contractures Tendon friction rubs Pitting scars on finger tips Cardiopulmonary manifestation Heart failure Pericarditis FVC <75% expected value DLCO low/decrease Muscle involvement Muscle weakness Higher creatine kinase level Myalgias or myopathy Arthritis/Arthralgias | \n
Genetics and biomarkers | \n
Anti-RNA polymerase III presence Anti-RNA polymerase I/II/III presence ELISA anti-RNA polymerase III ≥157 IU Anti-centromere absence Anti-nRNP presence ANA speckled immunofluorescence lipocalin-2 high levels [24] sCD147 high levels [25] angiogenin high levels endothelin-1 high levels HLA-DRB1*0407 HLA-DRB1*1304 | \n
Risk factors developed during SSc | \n
Skin changes acceleration Hemoglobin, thrombocyte decrease Cardiac involvement—new Pericarditis Congestive heart failure | \n
Drugs | \n
Cocaine [26] Glucocorticoid treatment Cyclosporine A Absence of calcium channel blocker | \n
Factors without evidence of SRC risk | \n
Previous blood pressure arise Abnormal dip-stick and light proteinuria Chronic elevation of serum creatinine Presence of antibodies: anti-topoisomerase, anti-centromere | \n
Clinical and laboratory predictors of scleroderma renal crisis and worse outcome. Adapted from Bose et al. [6].
SRC, scleroderma renal crisis; SSc, systemic sclerosis; FVC, forced lung vital capacity; DLCO, diffusing capacity for carbon monoxide; RNA, ribonucleic acid; ELISA, enzyme-linked immunosorbent assay; nRNP, nucleic ribonucleic protein; ANA, antinuclear antibodies; HLA, human leucocyte antigen.
SRC starts early, most often less than 4 years after the first SSc symptom, although SRC patients have minimal or even no skin changes at the time of the diagnosis of SRC. Males are proportionately more frequently affected than females [15].
\nOn the other hand, patients previously called as CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and Telangiectasia) rarely develop SRC. These patients are subgroup of lcSSc fundamentally [12].
\nWhen talking about risk factors of death, a history of renal crisis (HR 2.89), presence of proteinuria (HR 3.09), elevated acute phase reactants (HR 1.79), elevated creatine kinase (HR 1.73), and muscle weakness (HR 1.55) were associated with decreased survival [5, 16]. On the other hand, since the introduction of ACE inhibitors, renal crisis appears to have become an increasingly less frequent terminal event [4]. In EUSTAR cohort, except one individual, all patients dying from renal crisis were on an ACE inhibitor at the time of death. Prednisone equivalents above 15 mg daily have been implicated in exacerbating SRC [5].
\nSeveral retrospective studies suggest that glucocorticoids are associated with a higher risk of SRC. Blood pressure and renal function should be carefully monitored in patients with SSc treated with glucocorticoids [17]. Evidence regarding the impact of steroid use on the development of SRC comes mainly from retrospective studies, most of which showed significant association between steroid exposure and the occurrence of SRC [11, 15, 18, 19, 20, 21, 22].
\nA retrospective analysis including 140 patients with SRC showed that high doses of steroids (prednisone ≥30 mg/day) were used frequently in patients with SSc with normotensive SRC (64%) as compared with those with hypertensive SRC (16%) suggesting an association between the use of high-dose steroids and the risk of normotensive SRC, which is associated with worse prognosis [11].
\nGlucocorticoids are routinely used for the management of interstitial lung disease, puffy fingers, and skin involvement. These indications are not recommended (because of insufficient evidence of efficacy); however, the experts recognize their use in everyday practice in the management of inflammatory manifestations such as musculoskeletal involvement (arthritis, tendonitis, myositis—in overlap with idiopathic inflammatory myopaties), pericarditis, pleuritis (in overlap with SLE), nonspecific symptoms such as skin itching/burning, fatigue, and appetite (with empiric basis) [17, 23]. Considering the potential risk of SRC associated with steroid use, the experts recommend that patients with SSc treated with steroids should be carefully monitored with respect to the development of SRC [17].
\nIt can be summarized that glucocorticoids have a very narrow or no therapeutic opportunity in SSc.
\nSometimes SRC symptoms are nonspecific, for example, fatigue or not feeling well. Typically, patients complain of severe headache, blurred vision, or other encephalopathic symptoms with the onset of accelerated hypertension. Seizures may be also an early finding [1].
\nMost patients have striking increase of blood pressure at the onset of SRC. Above 90% patients have blood pressure levels >150/90 mm Hg, 30% have diastolic pressure >120 mm Hg, and <10% of SSc have a normal blood pressure. In addition to thinking about absolute values, clinically important risk factors arise of 30 mmHg systolic and 20 mmHg diastolic blood pressure (repeatedly measured) [1].
\nAcute kidney injury is defined as any of the following: increase in serum creatinine by >26.5 μmol/L (> 0.3 mg/dl) within 48 hours; increase in serum creatinine to >1.5 times baseline, which is known or presumed to have occurred within the prior 7 days, and urine volume <0.5 ml/kg/h for 6 hours. This is the definition of acute kidney injury from the Kidney Disease Improving Global Outcomes (KDIGO) guidelines [27].
\nPatients with SRC often present with congestive heart failure presented as dyspnea, paroxysmal nocturnal dyspnea or pulmonary edema, serious ventricular arrhythmias, cardiac arrest, or large pericardial effusion [11]. Interestingly, this is primarily owing to the stress of hypertension on the heart, effects of hyperreninemia, and fluid overload secondary to oliguric renal failure. Some patients have primary scleroderma myocardial involvement contributing to these consecutive insults [1].
\nAcute pericarditis is diagnosed if the patient has at least 2 of the 4 following criteria: (1) pericarditis chest pain; (2) pericardial rub; (3) new widespread ST-elevation or PR depression on electrocardiogram; (4) pericardial effusion (new or worsening) on cardiac echocardiography [1].
\nPulmonary hemorrhage is a rare life-threatening status, which has occurred in several of SRC patients [10]. Etiopathogenesis is associated with pulmonary edema and hemorrhagic diathesis. In differential diagnosis, diffuse alveolar hemorrhagia and acute renal failure were rarely observed in cases of ANCA systemic vasculitis and SSc overlaps [28].
\nTypically, hypertensive retinopathy (hemorrhages, hard and soft (cotton wool) exudates, and/or disc edema, not attributable to other causes), confirmed by an ophthalmologist, is observed. Hypertensive encephalopathy is characterized by headache, altered mental status, seizures, visual disturbances, and/or other focal or diffuse neurologic signs not attributable to other causes. Acute congestive heart failure is characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) [1, 6].
\nAntinuclear antibodies (ANA) are hallmark of connective tissue diseases. In case of Raynaud phenomenon, puffy fingers, nailfold capillaroscopy finding with typical microvascular changes, and ANA can alert to the very early diagnosis of SSc and may determine etiology of malignant hypertension. ANA are seen in 95% of SSc.
\nThe presence of scleroderma-specific antibodies may confirm SSc diagnosis, anti-topoisomerase I predicts diffuse SSc, but only 10% of SRC has anti-topoisomerase I positivity [6, 29] (Figure 6).
\nDiagram showing subsets of systemic sclerosis associated with kidney involvement stratified by antibodies. Colored areas represent approximated proportion in patients. Adapted from Kuwana M and Medsger A [35]. SSc, systemic sclerosis; SRC, dSSc, diffuse cutaneous systemic sclerosis; lSSc, limited cutaneous systemic sclerosis; scleroderma renal crisis; anti-RNA polymerase III, anti-ribonucleic acid polymerase III antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; anti-ds DNA, antibodies against double-stranded (ds) DNA.
Anti-RNA polymerase III is a scleroderma-specific antibody and is seen only in diffuse scleroderma. About 24–33% of these patients develop SRC [30, 31, 32]. It was showed that anti-RNA polymerase is strongly associated with SRC, OR 6.4 [33]. This statement is valid with the exception of geographical variability. For example, the difference in prevalence of autoantibodies among SRC patients between the Italian and other population might originate from the lower prevalence of anti-RNA polymerase III among Italians [34]. Anti-RNA polymerase III is associated with worse prognosis of SRC including Dialysis, persistence on dialysis, and survival [1].
\nSRC is a disease characterized by thrombotic microangiopathy with typical blood laboratory findings—new or worsening anemia, presence of schistocytes or other red blood cell fragments in peripheral blood smear, and thrombocytopenia <100.000, confirmed by manual smear. Typical features are laboratory evidence of hemolysis, including elevated lactate dehydrogenase, reticulocytosis, and/or low/absent haptoglobin and negative direct anti-globulin test. In differential diagnosis, other types of thrombotic microangiopathies need to be excluded (see Table 3). In some cases, thrombotic thrombocytopenic purpura has been reported in scleroderma patients, but it is unclear whether it was an isolated coexisting disease or a different interpretation of SRC [1, 6, 36].
\nHistory and condition | \nScleroderma renal crisis | \nCAPS | \nTTP-HUS | \nHELLP syndrome | \nSepsis | \nDIC | \nHIT | \n
---|---|---|---|---|---|---|---|
Previous history | \nSystemic sclerosis | \nAPS/SLE/malignancy/pregnancy | \nMalignancy/non | \npregnancy | \ninfection | \nInfection/malignancy | \nHeparin exposure | \n
Thrombosis | \nSmall vessels | \nLarge/small vessels | \nSmall vessels | \nSmall vessels | \nLarge/small vessels | \nSmall vessels | \nLarge/small vessels | \n
Hemolytic anemia | \n+ | \n−/+ | \n++ | \n+ | \n−/+ | \n−/+ | \n— | \n
Schistocytes | \n+ | \n−/+ | \n++ | \n+ | \n−/+ | \n−/+ | \n— | \n
Fibrinogen | \nNormal/high | \nNormal/high | \nNormal/high | \nNormal/high | \nNormal/low | \nNormal/low | \nNormal/high | \n
Typical antibodies | \nanti-RNA polymerase III | \naPL | \nADAMTS13 | \nNone | \nNone | \nNone | \nAnti-PF-4 | \n
Differential diagnosis of thrombotic microangiopathies from the view of scleroderma renal crisis. Adapted from Cervera et al. [37].
TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes and low platelets syndrome; HIT, heparin-induced thrombocytopenia; APS, antiphospholipid syndrome; CAPS, catastrophic antiphospholipid syndrome; SLE, systemic lupus erythematosus; aPL, antiphospholipid antibodies; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; PF-4, platelet factor 4.
The most common differential diagnoses are
anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis,
lupus nephritis, and
diseases associated with thrombotic microangiopathy (Table 4).
Event | \nDifferences from SRC | \n
---|---|
Essential hypertension | \nWithout acute renal failure | \n
ANCA-associated glomerulonephritis | \nANCA positivity, significant Proteinuria, hematuria [38] | \n
Overlaps with connective tissue disease with glomerulonephritis (SLE) | \nAnti-dsDNA positivity, other CTD-specific antibodies | \n
Renal artery stenosis | \nAbsence of systemic symptoms | \n
Thrombotic microangiopathies | \n\n |
Pre-eclampsia | \nPregnancy | \n
Hemolytic uremic syndrome | \nShigella toxin | \n
Thrombocytic thrombocytopenic purpura | \nADAMTS13 antibody | \n
Catastrophic antiphospholipid syndrome | \nAntiphospholipid antibodies | \n
Heparin-induced thrombocytopenia | \nHeparin treatment | \n
Differential diagnosis of scleroderma renal crisis. Adapted from Bose et al. [6].
Other conditions: membranous nephropathy, drug-induced nephropathies (e.g., cyclosporin A), other vasculitis (e.g., polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), oxalate nephropathy, membranoproliferative nephropathy, pre-renal causes (e.g., sepsis, dehydration, and cardiac or pulmonary vascular involvement), and isolated renal abnormalities. SRC, scleroderma renal crisis; ANCA, antibodies against neutrophils; SLE, systemic lupus erythematosus; CTD, connective tissue diseases; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
Thrombotic thrombocytopenic purpura (TTP) /hemolytic-uremic syndrome (HUS)/disseminated intravascular coagulation (DIC)/heparin-induced thrombocytopenia (HIT)/ pre-eclampsia or HELLP syndrome refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes, and low platelets/catastrophic antiphospholipid syndrome (CAPS), etc. [37].
\nOther differential diagnoses reported included membranous and membranoproliferative nephropathies, other vasculitis (including polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), drug-induced nephropathies (due to D-penicillamine or cyclosporin A), oxalate nephropathy, renal artery stenosis, and pre-renal causes (e.g., sepsis and dehydration) [10].
\nDespite significant decrease in incidence of SRC, no reliable preventive measures were identified. To decrease the risk of SRC development, we have to identify patients at high risk. Risk factors are discussed above (see chapter “Predictive and Risk Factors“), and we should take special caution in patients with dSS in the early stages of the disease (less than 5 years from diagnosis) with rapid progression of skin thickening, palpable tendon friction rubs, and anti-RNAP III antibodies [39]. Clinically, most important modifiable factor seems to be glucocorticoid treatment. Doses as high as 15 mg of prednisone are associated with increased incidence of SRC in several studies (see below).
\nPatients at risk should have their blood pressure controlled well. However, ACE inhibitors that are recommended for SRC treatment have not been shown to have protective effect before SRC onset and do not improve outcome of SRC [18, 19]. On the other hand, there are some reports of negative impact of ACE inhibitors on worse outcome of SRC, if ACE inhibitors were used in prevention of SRC [1, 40].
\nTherefore, other antihypertensive drugs should be used to treat primary hypertension in these patients. Calcium channel blockers are a preferred option, as these drugs are effective in controlling blood pressure and a positive vasodilatory effect [41].
\nEarly diagnosis and treatment can significantly improve prognosis of the patients. Patients at risk should be instructed to monitor blood pressure at home at least twice a week. They should report sudden increase in blood pressure and blood pressure above 140/90 mmHg. These patients should have their blood pressure quickly normalized and should be evaluated for possible SRC development (evaluation of kidney function, presence of MAHA, etc.).
\nCurrent treatment of SSc focuses on broad-spectrum immunosuppression or organ-based therapy for separate manifestations such as lung fibrosis, skin and gastrointestinal involvement, pulmonary or systemic hypertension, and kidney impairment [1]. The treatment of SRC is based on three main principles: causal treatment with ACE inhibitors, methods of renal function replacement, and plasma exchange in some patients. For organ complications, supportive treatment is used. SRC without treatment is often lethal. SRC patients should be treated immediately and aggressively with hospitalization and under careful control (Figure 7) [1]. It is advisable to admit patients with symptomatic hypertension to intensive care units.
\nManagement of scleroderma renal crisis, adapted from Lynch et al. [50]. ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; HDU, high dependency unit; ITU, intensive therapy unit; MAP, mean arterial pressure; SBP, systolic blood pressure.
The key to improved outcome is treatment with ACE inhibitors. It should be initiated as soon as possible. Captopril is the preferred option. It has been used in most studies and its short-acting character enables good titration at the start of the treatment. It is usually necessary to use very high doses. Blood pressure should be brought back to normal levels within 2–4 days.
\nACE inhibitors have complex effect and decrease blood pressure and plasma renin activity. The dramatic response to therapeutic inhibition of the renin-angiotensin system in SRC implicates renin overproduction as a central part of the pathogenesis of SRC [1, 42].
\nSeveral cohort studies showed benefit in survival with the use of ACE inhibitors in patients with SRC. The experts recommend immediate use of ACE inhibitors in the treatment of SRC [11, 17, 18, 19, 29, 43, 44, 45, 46, 47, 48]. Prospective analysis of 108 patients with SRC has suggested that patients on ACE inhibitors (captopril in 47 and enalapril in 8) had a significantly better 1 year survival rate (76%) and 5 years (66%) compared to patients without ACE inhibitors (15% at one and 10% at 5 years, respectively). Treatment with ACE inhibitors was significantly associated with better survival in SRC, after adjustment for age and blood pressure (p < 0.001) [29, 49, 50]. Two recent retrospective studies including 91 and 110 patients with SRC, respectively, the majority of whom (91 and 98% respectively) were treated with ACE inhibitors and/or angiotensin receptor antagonists (ARA), reported survival rates from 71–82% at 1 year, 59–60% at 5 years, and 42–47% at 10 years [19, 47]. Other anti-hypertensive agents may be considered for management of refractory hypertension in conjunction with an ACE inhibitor in SRC, including ARA, calcium channel blockers, doxazosin, and clonidine [1, 49]. Beta-blockers are not appropriate, as they affect peripheral circulation.
\nIt can be summarized that survival benefit was shown with the use of ACE inhibitors in patients with SRC. Experts recommend immediate use of ACE inhibitors in the treatment of SRC [17].
\nA patient with SRC is, from a definition, the one with acute kidney injury and should be managed in cooperation with a nephrologist. Thus, recommendation for acute kidney injury should be applied including regular monitoring of kidney function, minimization of nephrotoxic medication, etc. During first days of SRC treatment, serum creatinine levels usually increase. This is an anticipated decrease in glomerular filtration that should not discourage us from intensive blood pressure control [27].
\nRenal replacement therapy should be initiated if necessary. Both hemodialysis and peritoneal dialysis are possible alternatives. However, hemodialysis is a preferred option. ACE inhibitor treatment should continue long term, even in patients on chronic renal replacement therapy, especially in patients with possible recovery of renal function.
\nIn chronic hemodialysis patients, kidney transplantation has to be considered. There are two particular details in SSc patients that should be discussed: first, there is a possibility of late recovery of kidney function and, second, there is historically reported bad outcome of transplanted SSc patients. Indeed, patients with SRC may recover renal function up to 3 years after the crisis, most often within 12–18 months [50]. Thus, many authors recommend that decision to transplant should not be made before 2 years after SRC onset [17]. Patients after SRC on hemodialysis treatment should therefore be regularly checked for signs of recovery of kidney function. But in general, postponing kidney transplant in hemodialysis patients could worsen their prognosis. It seems prudent that in patients without significant residual renal function, without signs of kidney recovery and unfavorable findings on kidney biopsy (if done) such as vascular thrombosis and glomerular ischemic collapse, we consider kidney transplant in 6 months from SRC [51].
\nOlder studies reported bad outcome of SSc patients after kidney transplant compared to patients with other causes of kidney failure. However, recent studies have shown excellent patient and graft survival [52].
\nGenerally, on the other hand, long-term dialysis increases the risk of death. Independent of the underlying disease, dialysis increases the risk of infection (in patients undergoing peritoneal dialysis) and, over the long term, enhances the risk of vascular calcification and atherosclerosis. In patients on chronic dialysis, kidney transplantation has to be considered [53].
\nIn a series of 260 SSc patients who underwent renal transplantation in the United States, their 5-year graft-survival rate was 56.7% [53]. In that study, the risk of SRC recurrence was higher for patients with early renal insufficiency following SRC onset. Recurrent SRC in the allograft may be predicted by the same previously described risk factors [53, 54, 55].
\nFor those with recurrent SRC, the time of onset following transplantation is not known. Recurrence usually happens within the first few months to the first 1–2 years after transplantation [53, 54].
\nKidney transplantation should therefore be considered in all SSc patients with the need of renal replacement therapy. What has not changed over the last decade is that only small percentage of patients with SSc is transplanted due to severe extrarenal disease. Thorough work-up before enrolling a patient on waiting list is warranted.
\nBoth recurrence of SRC after kidney transplantation and graft loss due to SRC recurrence have been reported. Recurrence rate is fortunately low (8.8%) and patients after kidney transplant should be monitored similarly to patients with SSc at high risk of SRC development [52].
\nImmunosuppression given to SSc patients after kidney transplant alters the course of the disease. Most of the patients after kidney transplant have stable disease or even improve symptoms. Regarding immunosuppressive regimens after kidney transplant, it is difficult to make any evidence-based conclusions. Most patients were treated with high-dose steroids at the time of transplantation followed by long-term low doses in combination with calcineurin inhibitors and mycophenolate mofetil. A significant number of patients were weaned from steroids with reasonable outcome, but recommendations cannot be made due to limited number of patients [52].
\nPlasma exchange, which has been proposed for thrombotic microangiopathy, has not demonstrated efficacy and should not be prescribed, with the exception of the rare SRC patients who might develop thrombotic microangiopathy associated with anti-ADAMTS-13 antibodies [54]. There are no clinical trial data for use of plasma exchange in SRC.
\nClinically relevant renal involvement (non-SRC) in SSc is uncommon [55]. Asymptomatic and slowly progressive renal involvement is present in 60–80% of SSc patients. In more than half of asymptomatic SSc patients, renal function demonstrates clinical markers of renal damage (proteinuria, elevation of serum creatinine, hypertension, etc.) [32, 56, 57, 58]. These patients presented with evidence of underlying chronic renal disease but without confounding illnesses such as diabetes or hypertension existing prior to the onset of their SSc. Histological findings showed expressions of fibrillar collagens. In some SSc cases, drug exposure may explain interstitial kidney changes [6]. It is unclear whether SSc cases are more susceptible to this, but interstitial nephritis remains an important differential diagnosis.
\nGlomerulonephritis occurs in the context of overlap connective tissue disease or systemic vasculitis. In other words, SSc should be associated with other immunopathological diseases presented by glomerulonephritis, mainly systemic lupus erythematosus and ANCA-associated glomerulonephritis [59].
\nCirculating antimyeloperoxidase antibodies have been reported in several patients with dcSSc associated with necrotizing and crescentic glomerulonephritis [1, 58]. A study of 81 SSc patients with renal impairment found 2 patients with lcSSc with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) along with circulating IgG and IgM antimyeloperoxidase antibodies. After screening for ANCA in SSc by indirect immunofluorescence, the levels of IgM and IgG anti-MPO antibodies in 8 patients (8%) with SSc were determined by ELISA [60]. In conclusion, the presence of ANCA in SSc patients should predict ANCA-associated vasculitis. The treatment of these associated glomerulonephritis is managed according to the principles of treatment of the overlapping renal diseases (Figure 8).
\n\nNormotensive patient with systemic sclerosis and acute renal failure underwent renal biopsy. End-stage kidney disease: crescentic glomerulonephritis showing fibrous crescents. A mixed mononuclear cell infiltrate and considerable tubular loss are shown. Hematoxylin-eosin staining, magnification 200 times. Courtesy of Miroslav Podhola, MD., PhD., Department of Pathology, Faculty of Medicine in Hradec Kralove, Charles University.
SRC is a rare manifestation with dramatic clinical picture and high morbidity and mortality. Current strategies to reduce the associated morbidity and mortality include identification of at-risk patients to aid early diagnosis. Caution should be exercised in diagnosis of SSc cases with serological features of renal disease including anti-RNA polymerase III autoantibodies, for non-SRC renal disease SLE serology and ANCA positivity. ACE inhibitor therapy should be lifelong in all SRC patients. Prompt initiation of ACE inhibitors stays a key point in SRC therapy. New therapeutic possibilities are needed.
\nThis work was supported by MH CZ—DRO UHHK, grant number 00179906; Charles University research projects [PROGRES Q40-15]; and MHCR 023728 and AZV-16-33542A.
\nThis chapter reviews the methods of supramolecular chemistry and cryochemistry applied to study hybrid nanostructures and nanosized aggregates formed on plasmonic metals (silver and copper) and some mesogenic (liquid crystalline) compounds, which, in certain temperature ranges, reveal various liquid crystalline mesophases—orientationally ordered nematics, smectics with translationally ordered layer structure, and cholesterics exhibiting the space helix structures due to the chirality of their molecular structure and specifics of their helix supramolecular ordering. Attention was also paid to the peculiarities of morphological and structural behavior of such hybrid nanosystems, of their optical and adsorptive properties as well as perspectives of their possible applications.
\nHybrid nanosystems comprising nanosized metal particles stabilized in functionalized organic matrices are scientifically interesting due to their highly promising applications in nanoelectronics, photonics, and sensor systems [1, 2, 3, 4, 5, 6]. The use of mesogenic compounds in different liquid crystalline states as soft ordered template matrices opens new possibilities for the synthesis of anisotropic metal particles and their highly ordered assemblies. The presence of metal atoms and ions in liquid crystalline systems significantly extended the possible practical areas of their exploitation. The most prospective are hybrid metal-mesogenic nanosystems, combining molecular ordering of mesogenic matrix compounds and quantum-size properties of nanometals, which are different from both the characteristics of the single atoms and the properties of bulk materials. The properties of such systems are dependent not only on the size and shape of individual nanoparticles of the formed system, but also on the character of their joint organization and formation of the hybrid ordered structure [7, 8]. Among different methods of metal particles’ incorporation into the organic systems and formation of hybrid nanosystems, the most original and useful are methods of low-temperature condensation of metal atoms with the molecular beam of organic component’s vapors under high-vacuum conditions [9, 10]. The use of low temperatures and technique of vacuum condensation of metal atoms and organic molecular beams on the cooled support surfaces allowed researchers to stabilize and study such highly active species as metal clusters and nanoparticles and their labile complexes. This approach allowed us to realize the formation of hybrid nanosystems by bottom-up method and to carry out the directed metal atom and small clusters aggregation, controlled by structural and dynamic properties of molecular organized matrices, and also to create new ordered assemblies of nanoparticles.
\nIn this work, the formation of new hybrid metal-mesogenic nanosystems was exemplified by two d-metals of the 11th group—silver and copper with mesogenic derivatives of long-chain alkylcyanobiphenyls. Nanoparticles of silver and copper possess the intensive plasmonic bands in the visible region of spectrum and can be used for the visualization and marking of different biological objects. Mesogenic compounds of the alkylcyanobiphenyl row are widely used nowadays as components of active layers for liquid crystalline displays and indicators. These compounds form ordered liquid crystalline phases of two types—nematic, characterized by the existence of molecular orientations of long-range order, and smectic—with layered molecular ordering. The existence of molecular associates and formation of dimeric structures in solid and liquid crystalline phases is known for these compounds at low temperatures. They form several metastable and stable solid phases with a local structure similar to the liquid crystalline mesophases with a different molecular organization [11, 12]. A terminal cyano group and an aromatic core of the molecules can be considered as ligands suitable for the formation of complexes of π- and σ-types with atoms and clusters of the metals under consideration [13].
\nControlled formation of anisometric nanoparticles and ordered hybrid nanostructures is one of the main objectives of this work. The role and mutual influence of self-organization processes of metal species and organic component’s molecules were considered. The phase-structural transitions and physico-chemical properties that appear for new hybrid metal-mesogenic nanosystems were demonstrated on the example of a combination of silver and copper metal nanoparticles formed in mesogenic matrices of long-chain (n ≥ 5) alkylcyanobiphenyls 4-pentyl-4-cyanobiphenyl (5CB) and 4-octyl-4-cyanobiphenyl (8CB).
\nMesogenic derivatives of cholesterol possess unique liquid crystalline mesophases named cholesteric mesophases at definite temperature ranges [1]. The molecules in such a mesophase are arranged in prolonged 3D helix structures with special optical properties depending on the pitch of the helix, such as selective reflection of visible light. Introduction of metal atoms and clusters in cholesteric mesophase changes the intermolecular interactions in the system and leads to the induction of new liquid crystalline and isotropic phases. We can also find the formation of self-assembled nanosized aggregates with different morphology and hybrid nanostructures, including metal species of different sizes arranged by a mesogenic matrix in highly ordered assemblies with modified optical properties. Special attention will be paid to analyzing the possibilities of their use in modulation of optical signals and obtaining systems with tunable optical plasmonic resonance.
\nSelf-organization of nanosized metal particles in highly ordered assemblies with definite structural and morphological characteristics is nowadays one of the most promising areas of nanoscience and nanotechnology [2, 3]. The unique quantum-size properties and the appearance of new collective modes open new possibilities for their application in such fields as microelectronics, optics, catalysis, information recording systems, and data storage systems [4, 5, 7]. The physical and chemical properties of such nanohybrid systems depend both on the size and shape of the structural elements (nanoparticles), and on the manner of their organization into the joint structure [8, 9]. Development of new synthesis methods of nanohybrid aggregates possessing special order in regular placement of the particles of the same size is an important task in modern nanochemistry. For the synthesis of nanoparticles having a certain size, it is necessary to physically or chemically isolate nanoparticles from one another and from the external environment to prevent aggregation. In many cases, the stability of such systems is achieved through the introduction of functionalized organic ligands aryl- and alkylthiols, organic amines, alcohols, and other compounds capable of specific interactions with the surface of the nanoparticles [10, 11]. Hybrid nanosystems including biomolecules or their chemical analogs attract the increasing interest of researchers due to their compatibility with natural systems [12, 13, 14]. In the present chapter, we show the possibilities of using two new silver-containing nanosystems based on biomolecule of cholesterol and its heteroatomic analog—thiocholesterol. Supramolecular organization of the ligand molecules allows us to use the obtained nanoparticles for self-assembling in binary superlattices and for the formation of ordered 1D-, 2D-, and 3D nanostructures.
\nCholesterol and its derivatives are optically active molecules and form helical liquid crystalline structures—cholesteric mesophases—at definite conditions. It is known that the effects of “guest-host” interactions are very important for the practical applications of composite liquid crystalline systems, including guest molecules of organic and inorganic compounds [15, 16]. At the same time, these compounds contain such functional groups as –OH and –SH, which are able to the effective interaction with the surface atoms of metal nanoparticles and form a mesogenic ligand stabilizing and selecting layers on the surface of metal nanoparticles. Recently, we have intensively developed investigations on the creation of new methods of producing hybrid metal-mesogenic nanosystems and the study of their physical and chemical properties [17, 18, 19, 20].
\nTEM study of the film samples of hybrid nanosystems “silver-4-pentyl-4-cyanobiphenyl” (Ag/5CB) and “copper-4-pentyl-4-cyanobiphenyl” (Cu/5CB), obtained by low-temperature co-deposition of components and annealing at 150–200 K for 1–2 h, shows the possibility of the formation and stabilization of mesogenic matrix by 5СВ practically monodispersed spherical metal nanoparticles 1–2 nm in size (Figure 1). These metal species were formed in the solid nanostructured matrix of 5CB as a result of thermal decomposition of unstable dimeric biligand π-complexes of metal atoms M(5CB)2 [16]. The metal atoms liberated by degradation of the complexes localize and can interact with each other in the local areas formed by mobile alkyl chains of a terminal substituent in 5CB dimeric structures existing at such low temperatures. Results of the study of different small areas of the film sample by selected area electron diffraction (SAED) show the formation of metal nanoparticles with fcc lattice. The size of metal nanoparticles formed in mesogenic matrices at these temperatures was close to the critical crystal size of the metal particles.
\nTEM pictures and electronic diffraction of the samples, including silver nanoparticles stabilized in mesogenic 5СВ matrix at 200 K and histogram of their size distribution.
These small metal particles are stable at low temperatures under the conditions of limited molecular mobility of mesogenic matrix particles and can play a role of the initial crystalline particles (the embryo of a new phase) by raising the temperature. These small metal crystals appear in ESR spectra of the samples as broadened singlets with g-factor close to the value for free electron, ge = 2003, which could be referred to conducting electrons spin resonance in metal nanosized species [16].
\nBy annealing the samples from 90 up to 150 K, the relative intensity of the central component in ESR spectra increases, which reveals the thermal decomposition of the metastable complexes and the simultaneous growth of metal nanoclusters. UV-Vis spectroscopic study of silver/CB and copper/CB systems showed the appearance of new plasmonic absorbance bands in the visible region with a maximum at 400 and 560 nm, respectively.
\nOn further heating of the samples up to temperatures more than 200 K, matrix crystallization process took place, which led to a sharp increase of matrix molecular mobility and rapid coalescence of nanoclusters followed by forming bigger aggregates, which was not recorded by the ESR technique. Such thermal behavior of the hybrid system can be deduced from the specifics of self-assembling processes and supramolecular organization of mesogenic cyanobiphenyl matrix at different temperatures. The combination of rigid aromatic core and flexible hydrocarbon chains of terminal substituents in ligand molecules leads to the formation of dimeric cyanophenyl structures in solid and liquid crystalline states at low temperatures. Such supramolecular structures could stabilize metal atoms due to the formation of metastable complexes. Thermal degradation of the complexes by increasing the temperature of the co-condensate samples followed by metal atoms escape into more soft domains formed by hydrocarbon chains and their rapid aggregation. Stabilization of nanosized metal clusters of size 1–2 nm formed at this stage is possible due to their low diffusion mobility in the solid cyanophenyl matrix. Warming of co-condensate systems up to the temperatures more than 200 K (T > 200 K), corresponding to CB crystallization, causes matrix softening and rise in the translational mobility of matrix molecules. This process is followed by metal nanoclusters’ coalescence and formation of higher nanoparticles. Rapid heating up of the co-condensates up to the room temperature followed by the phase transition of the system in nematic (orientationally ordered molecular long-axes) and smectic phases (molecular ordering layered structure) led to the performable formation of the anisometric nanoparticles. In metastable crystal state of 5СВ at 273–293 K, the temperatures close to the crystal to nematic phase transition point for hybrid metal-mesogenic “Ag-5CB” nanosystem, under the conditions of maximal ordering of liquid crystalline matrix molecules, the directed growth of highly anisotropic metal nanorods took place, their lengths (l, nm) were more than 200 nm and their widths (d, nm) were about 15 nm, so anisometric l/d ratio was more than 10 (Figure 2). Mechanism of such almost single-dimensional growth of metal nanorods, in this case, is connected with the rapid growth of the molecular matrix mobility and maintaining high orientational order of the system.
\nTEM pictures of silver nanorods, growing in 5СВ matrix at 273–290 K.
Study of the samples by X-ray diffraction shows the exact crystal character of metal nanoparticles formed at these conditions. The samples possess texture that appeared due to the directed growth of rods along the crystallographic plane (100) and perpendicular to crystallographic plane (111). Observed mechanism of nanoparticles’ growth can be explained by concurrent interaction of terminal functional cyano (CN) group of ligand molecules with metal atoms belonging to different crystallographic planes of forming nanoparticles. The interaction of ligand molecules with metal centers of highly packed bulky Ag (111) is slower in comparison with more loose Ag (100); so, the preferential growth of nanorods can be realized just in this direction due to the effective accession of small metal clusters and atom-by-atom addition formed in newly added layers and formation of highly anisometric metal nanoparticles.
\nIt was shown by the combination of transmission electron microscopy (TEM) data with the results of selected area electron diffraction (SAED) and X-ray diffraction that hybrid metal-mesogenic nanosystems formed by low-temperature co-condensation of silver and copper with mesogenic cyanobiphenyls and followed by controlled annealing of the samples constitute of nanohybrid materials including metal nanoparticles stabilized and organized by matrix of mesogenic ligands. Depending on the phase of hybrid nanosystems Ag/5CB and Ag/8CB, nanoparticles of different sizes and morphology—globular with main diameter 15 nm, anisometric rods, and flat 2D aggregates—were formed. Rapid heating of metal-mesogenic co-condensate samples up to 313 K was followed by phase transition of the hybrid system to the isotropic state and formation of globular metal particles of average diameter 15 nm. The data of FTIR study of the system show the formation of monomeric alkylcyanobiphenyl molecules stabilizing layer on the surface of nanoparticles due to donor-acceptor interactions of terminal CN group of ligand with surface metal atoms. The rising metal concentration and carrying out the nanoparticles’ self-assembling processes in orientationally ordered nematic mesophase led to the formation of anisometric metal nanoparticles (anisometric factor l/d = 3–4) and their highly ordered assemblies. The results of AFM study of the samples show the formation of linear aggregates and regular orientationally ordered structures of anisometric nanoparticles in nematic phase 5СВ at 300 K (Figure 3). Histogram of bimodal size distribution for metal nanoparticles in this case is also presented in Figure 3.
\nAn AFM image (tapping mode) of the sample of hybrid metal-mesogenic nanosystem “Ag-5CB” (1/10) in nematic phase 5СВ (left) and histogram of size distribution (right) for silver nanoparticles, red—cross size of nanoparticles, blue—linear length of nanoparticles.
Using higher homology 4-octyl-4-cyanobiphenyl (8CB) molecules as stabilizing ligands gives us the possibility to carry out metal nanoparticles’ formation in layered molecular structured smectic mesophase also. In this case, we saw the formation of quasi-fractal flat metal aggregates intercalated between smectic layers of 8CB due to higher interacting energy in the smectic layers and microphase segregation (Figure 4).
\nAn AFM image (tapping mode) of the sample of hybrid metal-mesogenic nanosystem “Ag-8CB” (1/10) in smectic phase.
Thus, fulfilling the self-organization and self-assembly processes during the formation of hybrid nanosystems in liquid-crystalline mesophases of different types led to the production of metal nanoparticles of different sizes and morphology and their supramolecular organization in highly ordered nanostructures, including anisometric nanoparticles and rod-like aggregates stabilized in nematic mesophases and flat 2D metal aggregates in layered structured smectic phases of long-chain alkylcyanobiphenyls. Increasing the ligand molecules’ concentration led to the stabilization of metal nanoparticles of smaller size. Increasing metal concentration in the orientationally ordered nematic system supported the formation of anisometric rod-like metal nanoparticles and their aggregates. The scheme of phase-structural states for Ag/5CB hybrid nanosystem indicating the conditions for the formation of metal nanoparticles with definite morphology is presented in Figure 5. This scheme is considered the combination of the result of thermal analysis, polythermal polarization spectroscopy, and electronic and atomic force microscopy.
\nThe scheme of phase-structural states for “silver-5CB” hybrid nanosystem: I—isotropic phase; II—two-phase region: isotropic phase including the fluctuations of nematic ordering; Ш—nematic phase; IV—the temperature region in nematic phase close to phase transition from crystalline to nematic; and V—solid phase at 150–200 K.
The data presented in Figure 5 show the formation of nanoparticles with different morphology and sizes, stabilized by mesogenic ligands depending on the phase of mesogenic matrix and metal concentration in the system. The shape of the particles is in general the result of competition between general tendency for the minimization of particle’s surface energy and elastic energy of liquid crystal. Rapid heating (more than 100 K/min) of the co-condensate Ag/5CB sample to temperatures of isotropic phase (T > 318 K)—region I—led to the formation and stabilization of global nanoparticles with d = (15 ± 10) nm. Transition to the nematic phase of 5CB gives us anisometric metal nanoparticles and their orientationally ordered assemblies—region III. In the bi-phase region II, including the co-existence of isotropic phase with fluctuations of nematic ordering, the formation of both isotropic globular and anisometric rods is possible. Maintaining the samples at 273–283 K and increasing the metal content in the sample from 1 up to 10 w/w % (region IV in Figure 5) led to the preferential growth of rod-like metal nanoparticles with l/d ratio more than 10. Small metal nanoparticles 1–2 nm in size are formed in diluted systems in the solid phase at 150–200 K.
\nThe layer-by-layer co-condensation of vapors of para-xylylene monomer, metal silver, and cyanobiphenyl ligand followed by controlled heating or UV irradiation of the sample led to the formation of hybrid metal-mesogenic compositions with varied metal contents from 1 up to 10 w/w %, encapsulated in polymer film:
The results of TEM study of the Ag/5CB samples encapsulated in poly-para-xylylene (PPX) films show that increasing metal contents in the sample up to 10 w/w% led to the growth and stabilization of elongated rod-like metal particles with anisometric ratio l/d more than 10 (where l is the length and d is the cross diameter of particles). X-ray diffraction pictures of the Ag/5CB (w/w 1:10) sample, formed at 200 K followed by annealing up to 450 K, are shown in Figure 6. The results obtained show the formation of metal nanoparticles with fcc lattice, with lattice constant similar to that of crystal silver, а = 0.408 nm; the crystallographic planes were identified as (111), (200), (220), and (311). TEM data for the Ag/5CB (10 w/w %) sample encapsulated in polymeric film showed the formation of regular nanostructures stabilized by liquid crystalline matrix of anisometric metal nanoparticles (Figure 7), and their optical spectra are presented in Figure 8. Optical spectra contained the intensive absorbance bands of bimodal plasmonic resonance of anisometric silver nanoparticles (Figure 8).
\nX-ray data for sample of hybrid metal-mesogenic nanosystem Ag/5CB (1:10), encapsulated in polymer (PPX) film at 450 K (а), 300 K (b), 250 K (c), and 200 K (d).
AFM data for the sample of hybrid metal-mesogenic nanosystem Ag/5CB (1:10 w/w%) encapsulated in poly-para-xylylene polymeric film.
An optical spectrum for the sample of hybrid metal-mesogenic nanosystem Ag/5CB (1:10 w/w %) encapsulated in poly-para-xylylene polymeric film.
The proposed method allows encapsulation from several molecular layers up to several microns. In the optical spectra of such hybrid metal-containing mesogenic systems encapsulated in PPX films at 300 K, the plasmonic bands appear at 420–440 and 500–600 nm, characteristic of the formation of silver nanoparticles and their ordered aggregates, respectively. Increasing the metal concentration led to the formation of anisometric rod-like particles with multimodal plasmonic resonance related to cross and linear resonance. The formation of rod-like metal nanoparticles with anisometric ratio l/d > 10 enhanced plasmonic absorbance in the long-wave spectral range (λ ≥ 650 nm). In this case, the value of dichroic ratio D!!/D⊥ in the plasmonic band for Ag/5CB (1:10) samples uniformly oriented by magnetic field rises by 5 times in comparison with pure 5CB samples. Optical properties of the samples are stable for several months.
\nHybrid “silver-cholesterol” and “silver-thiocholesterol” nanosystems were produced by cryochemical synthesis via low-temperature co-condensation of components’ vapors or two-phase chemical reduction of the silver nitrate salt by NaBH4 and metal-organic complex transferring into toluene environment using inter-phase zwitter-ionic carrier N+(C8H17)4Br− and functionalized cholesteric ligands [21, 22]. Cholesterol (a) and thiocholesterol (b) molecules were also used in order to form protective surface layers on silver nanoparticles formed in the system, their chemical structures are presented below.
The organic silver nanoparticle’s sols prepared after drying and dissolution had been used for FTIR-and UV-Vis spectroscopic studies. The FTIR spectra of the samples were recorded using Tensor II FTIR spectrometer Bruker (Germany), and UV-Vis spectra were recorded by the V770 spectrometer, JASCO (Japan). The chemical composition of the samples obtained was controlled using selected area electron diffraction (SAED) and direct chemical analysis by ICP-MS spectrometer. The internal structure of the samples and the size distribution of the stabilized silver particles were obtained using transmission electron microscopy (TEM) instrument LEO 912 AB Omega (Germany); differential scanning calorimetry (DSC) instrument STA 449C, Netzsch (Germany); and X-ray diffraction instrument D/MAX-2600, Rigaku (Japan).
\nUnderstanding the mechanism of interaction between metal species and stabilizing agents—cholesterol and thiocholesterol ligand molecules—was one of the purposes of this study. The most typical bands of O–H group stretching vibrations at ν = 3490–3500 cm−1 and O–H group δ-deformation vibrations at ν = 1090–1140 cm−1 and also of S–H group stretching vibrations at ν = 2540–2590 cm−1 are almost absent in the FTIR spectra of the silver-containing hybrid nanosystem’s samples, and the bands stretching vibrations for CH3–, CH2–, and S(O)–CH2 groups at ν = 2920–2880 cm−1 and ν = 1415–1440 cm−1 are appear in the spectra. This fact could be considered at the spectral confirmation of the interaction of the thioxy group of thiocholesterol ligand and hydroxy group of cholesterol ligand molecules with the surface atoms of silver nanoparticles [16] and of the existence of stabilizing ligand monolayers on the surface of the metal nanoparticles [17].
\nThe morphology and size distributions of metal species primarily formed in “silver-cholesterol-toluene” and “silver-thiocholesterol-toluene” triple hybrid nanosystems are presented in Figures 9A and B and 10A and B, respectively. The main diameter values of silver nanoparticles were d = (6.5 ± 1.5) nm for cholesterol-stabilized organosols of silver nanoparticles and d = (2.5 ± 0.5) nm for thiocholesterol-stabilized organosols of silver nanoparticles.
\nTEM pictures for silver nanoparticles stabilized by cholesterol (A) and thiocholesterol (B) ligand molecules.
Histograms of size distribution for silver nanoparticles stabilized by cholesterol (A) and thiocholesterol (B) ligand molecules.
The formation of dispersions of stabilized nanoparticles and their regular surface structures took place by withdrawal of organic solvent from the film samples. The chemical nature of stabilizing ligand molecules and concentration of metal nanoparticles in the hybrid system determined the manner of metal species packing in 2D- and 3D superlattices. By removing the organic solvent, the formation of 2D nanostructures with a hexagonal (Figure 9) or cubic symmetry was achieved (Figure 11).
\nTEM and SAED pictures of silver-thiocholesterol samples obtained by deposition from triple “silver-cholesterol-toluene” system [20].
The process of such ordered nanostructure formation can be described by the following scheme presented in Figure 12 [20]. It began from the formation of individual metal nanoparticles in highly diluted organic sols stabilized by cholesterol or its heteroatomic derivative thiocholesterol and by raising the metal nanoparticles’ concentration, which led to the production of 2D- and 3D nanoparticle superlattices with hexagonal and cubic symmetry.
\nThe scheme of formation of binary nanostructures of silver nanoparticles and thiocholesterol molecules in triple “silver-thiocholesterol-toluene” systems [20].
It is of interest that the interparticle distance (average distance between the centers of metal nanoparticles) in the nanostructures obtained is rather small and is practically equal to the size of organic layer shell from cholesterol or thiocholesterol molecules (about 2.5 nm). Such regular position of plasmonic metal small nanoparticles in highly ordered dielectric organic media promised possible applications of the hybrid systems obtained in nanooptics and molecular electronics.
\nBinary “silver-thiocholesterol” nanosystem, obtained after entire removal of the toluene solvent, was heated up to 70–80 C and then cooled down to ambient temperature. It possessed liquid crystalline cholesteric mesophase that could exist in a supercooled state for a long time. The formation of elongated nanotubular hybrid aggregates took place. The TEM pictures for the sample of the binary system stored at 293 K for 24 h for the silver nanoparticles formed in the system are presented in Figure 13.
\nTEM pictures for hybrid silver-thiocholesterol aggregates after 24 h of storage in liquid crystalline mesophase: general view (A) and internal structure (B) [22].
Supramolecular ordering of hybrid nanosystem included the interaction of the surface centers of silver nanoparticles with the functional groups of cholesterol and thiocholesterol ligands and their helix supramolecular ordering in cholesteric mesophase. The scheme of molecular interactions is presented in Figure 14.
\nThe scheme of silver-thiocholesterol tubular nanoaggregates formation.
There were intensive plasmonic bands of ligand-stabilized silver nanoparticles at 420–450 nm (Figure 15, curve 1) in the UV-Vis spectra of hybrid “silver-cholesterol” and “silver-thiocholesterol” nanosystems. Rising of metal contents led to the red shift of these bands due to specific interactions of silver nanoparticles with ligand molecules and particle-particle dipole-dipole interactions. In the optical spectra of binary “silver-thiocholesterol” system (Figure 15, curve 2) along with the plasmonic absorption of individual silver nanoparticles at λ = 450 nm, the long-wave absorption also appears at 770–1000 nm, which is characteristic for chain aggregates of silver nanoparticles [23]. The hybrid aggregates’ absorbance bands were shifted to the near-infrared region and it is important for possible applications in in vivo imaging and sensing of different biomedical objects.
\nOptical absorbance spectra: 1—highly diluted sols of silver nanoparticles stabilized by thiocholesterol in toluene and 2—linear aggregates, formed in liquid crystalline mesophase of hybrid “silver-thiocholesterol” system.
The chirality of active compounds is important for many biochemical processes [24, 25, 26], the study and separation of optical isomers of drugs are principal for pharmaceutical applications, and control of optical purity is necessary for the production of pharmaceutical components. Cholesterol and thiocholesterol ligands and their mesogenic derivatives are natural and modified chiral matrices, which adsorptive and selective properties only begin to study [27].
\nThe synthesis of hybrid nanoparticles with silver core and stabilizing cholesterol/thiocholesterol shell layer of chiral ligand thiocholesterol was produced by modified of borohydride reduction method [28], including reduction of silver ions Ag+ in bi-phase water-organic system in the presence of mesogenic ligands. This system was used to impregnate silica gel plates for thin-layer chromatography. The UV-Vis spectra of toluene sols of the hybrid system “silver-thiocholesterol” (Ag: L = 1:5) were recorded in silver concentration of range 0.2–2.0 mg/ml and show the characteristic silver nanoparticles’ plasmonic band at 450 nm. The intensity of absorbance grows linearly by increasing the concentration of nanoparticles.
\nThe selection of model optical isomers of tested compounds was made using silica plates modified by hybrid silver-thiocholesterol (Ag:L = 1:5) nanoparticles (Figure 16) with a concentration of 1.2 mg/ml. The chromatographic separation of tested substances was made using modified silica plates [29]. The eluent phase for the selection was chosen from several solvents that differed in their chemical structure and polarity—methanol, isopropanol, acetonitrile, acetone, and butyl acetate. It was shown that the most suitable eluent was the mixture acetonitrile/water (50:50 v/v), the yield mobility was found rising in the order: 1,1′-bi-2-naphtol <2,2′-diamino-1,1′-binaphtol (DABN) ≈ trifluoro antranyl ethanol (TFAE). The difference of the values of Rf was observed for S- and R-isomers of DABN and TFAE. The detection of the spots of separated enantiomers DABN and TFAE was made by UV irradiation at 360 nm of the chromatographic plates using the ability of these compounds for exhibiting fluorescence [30].
\nSchematic structure (a) of silica gel modified by silver nanoparticles stabilized by thiocholesterol (b).
The chromatographic separation was estimated by the value of Rf, which was calculated using the relation Rf = x/L, where x is the length, passed by the substance from the start line, and L is the length, passed by solvent up to front line [28]. The efficiency of separation was estimated by the value α (selection factor), which was calculated using the relation α = \n
Test substances | \nRf | \nα | \n
---|---|---|
2,2′-diamino-1,1′-binaphlene (R) | \n0.57 | \n1.56 | \n
2,2′-diamino-1,1′-binaphlene (S) | \n0.46 | \n|
1,1-bi-2-naphthol (R) | \n0.49 | \n1.07 | \n
1,1-bi-2-naphthol (S) | \n0.51 | \n|
TFA (R) | \n0.43 | \n1.56 | \n
ТFA (S) | \n0.54 | \n
The retention times (Rf) and separation factors (α) of test compounds in thin-layer chromatography experiments [31].
A new approach was proposed and realized for the formation of highly ordered hybrid metal-mesogenic nanostructures based on the mesogenic matrix-governed self-organization of atomic-molecular systems obtained by low-temperature condensation of metal and mesogenic components’ vapors followed by controlled annealing of the samples. The hybrid metal-mesogenic nanosystems have been obtained including plasmonic metal (silver and copper) nanoparticles stabilized and supramolecular structures organized by liquid crystalline matrix and their properties were studied in temperature range 80–350 K. The conditions that allowed the production of metal nanoparticles of different sizes and morphology were determined, and methods of creation of their ordered nanostructures using molecular self-organization and metal species self-assembly were developed.
\nLow-temperature co-deposition of metal (Ag, Cu) and mesogenic alkylcyanobiphenyl component (5CB, 8CB) vapors led to the formation of the first stage of metastable biligand complexes of metal atoms with functional CN group, stabilized in ligand matrices. Thermal degradation of the metastable complexes at 150–200 K led to the formation of small metal clusters, which initiate the growth of nanoparticles and their further aggregation and organization in anisotropic mesogenic matrix. The structural and dynamic properties of mesogenic matrix at different temperatures and different phases controlled metal atoms’ and small clusters’ self-assembling and aggregation and led to the formation of metal particles of different sizes and morphology and their ordered aggregates. The competition of the processes of matrix molecules self-association, metal atoms aggregation and metastable complexes formation between metal species of different size with ligand molecules and molecular aggregates determines the structure and physico-chemical properties of hybrid nanosystems formed in definite conditions. Highly ordered nanohybrid systems can be very promising for different applications in nanoelectronics and electro-optics, as they possess unusual optical and sensor properties.
\nLigand-stabilized silver nanoparticles were obtained by biphase chemical synthesis using biomolecule of cholesterol and its heteroatomic analog thiocholesterol. Regular 2D- and 3D superlattices with hexagonal or cubic ordering of almost monodispersed silver nanoparticles with main size d = (6.0 ± 1.5) nm for “silver-cholesterol” and d = (2.5 ± 0.5) nm for “silver-thiocholesterol” systems were obtained by removing the solvent from surface layers of triple “silver-cholesterol (thiocholesterol)-toluene” sols and for binary “silver-thiocholesterol” systems. Hybrid nanosized tubular silver-thiocholesterol aggregates with linear size (length) of more than 10 μm and only 15–20 nm wide including practically monosized silver nanoparticles of d = (2.5 ± 0.5) nm have been formed for binary silver-thiocholesterol system in cholesteric liquid crystalline mesophase.
\nThe optical properties of hybrid nanosystems obtained belong to the plasmon absorption of individual silver nanoparticles and also possess modified plasmonic bands of hybrid nanostructures and highly ordered nanoparticle superlattices formed under special concentration and temperature conditions. Such hybrid nanostructures should be of interest for the creation of new optical and electro-optical devices with adjustable light absorption and light reflection. Integrating silver nanoparticles of exact size and shape and their aggregates of definite morphology with biological molecules and blocks opens new perspectives for obtaining new bio-compatible instruments for imaging and sensing biological objects in living organisms and targeted medical therapy.
\nThe hybrid metal-mesogenic nanosystems obtained were also used as liquid crystalline component for modification of silica gel nanoparticles and production of chiral matrices for thin-film chromatography. The conditions that allowed the production of silica gel plates modified by chiral hybrid metal-mesogenic nanosystems from toluene sols were developed. The new chiral matrices for thin-film chromatography possessed enantioselectivity related to optical isomers of 2,2′-diamino-1,1′-binaphtol (DABN) and trifluoro antrenylethanol (TFAE). We have succeeded in selecting optical isomers of TFAE with selecting factor equal to 1.56. In the future, the hybrid silver-thiochlesterol systems obtained in this work can be used as chiral stationary phase also for high-performance liquid chromatography (HPLC). One can expect the higher values of selectivity effects due to the increasing pathway for selecting compounds in comparison with thin layer chromatography technique.
\nThe author would like to thank Dr. S.S. Abramchuk, Centre of Electronic Microscopy of M.V. Lomonosov Moscow State University, for TEM and SAED measurements, and Dr. A. S. Tikhomirov, NT MDT, for AFM measurements.
\nThe author appreciates the help and input of collaborators from Analytical Department of M.V. Lomonosov Moscow State University, and Dr. E.N. Shapovalova, Dr. N.B. Rozhmanova, and Prof. O.A. Shpigun for participation in analytical experiments and fruitful discussions.
\nThe work was financially supported by Russian Foundation of Basic Research (Grant Nos. 15-03-00792-a and 18-03-00730-a).
\nEdited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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