**2. Statins in type 2 diabetes—Friends or Foe?**

#### **2.1. Dyslipidemia is one of the criteria of metabolic syndrome, pre-stage of type 2 diabetes**

Prevalence of metabolic syndrome has been increasing with prevalence of obesity. The pathophysiology of metabolic syndrome is very complicated, but has been partially under‐ stood. It has been well documented metabolic syndrome is an important risk factor for cardiovascular diseases, especially heart diseases including heart failure and ischemic heart disease. Some studies have shown the prevalence of metabolic syndrome in the USA to be an estimated 34% of the adult population [15], and the prevalence increases with age. In addition, weight gain is associated with metabolic syndrome. Central obesity is the most important confounder of metabolic syndrome, therefore, waist circumference may represent the existence of metabolic syndrome (Table 1). Another key confounder of metabolic syndrome is insulin resistance [20, 21]. Hypertensive patients, even they are nonobese, show high prevalence of insulin resistance, and metabolic syndrome coexists. Usually, people with metabolic syndrome has higher risk of developing cardiac events by twice and diabetes by 5 times compared to individuals who do not have metabolic syndrome. Therefore, hypertensive patients, even not obese, with metabolic syndrome have very high risks of cardiac events and diabetes.

for these lipids' parameters phenotypes in the investigation using 2,000 genes.Genome-wide association studies (GWASs) have shown strong relationships between genetric polymor‐ phisms and lipids levels. Dyslipidemia may have, at least partly, determined genetic back‐ grounds, and understanding the heritability of dyslipidemia may help to control dyslipidemia. Dyslipidemia is known as one of the important causes for the atherogenic changes in cardio‐ vascular system, and results in very severe cardiovascular risk. Therefore, diabetes patients with dyslipidemia have much higher prevalence of mortality and morbidity of cardiovascular risks compared to diabetes patients without dyslipidemia. However, there have been a lot of discussions, especially required statins on type 2 diabetes, because statins increase the risk of new-onset type 2 diabetes mellitus [7-9]. Very recent genetic meta-analysis suggested that the increased risk of type 2 diabetes noted with statins is at least partially explained by 3-hy‐ droxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) inhibition [10]. The statins work in the liver to prevent the formation of cholesterol. This class of drugs are most effective at lowering the LDL- cholesterol, but also have modest effects on lowering triglycerides and raising HDL- cholesterol. There are several large cohort studies investigating the effects of statins on cardiovascular risks such as the Scandinavian Simvastatin Survival Study (4S) [11] and the Cholesterol and Recurrent Events (CARE) [12, 13] trial, however, the results are discordant. Some studies showed the drugs to reduce a patient's risk of cardiac events and stroke, outside of their ability to lower cholesterol levels. On the other hand, the statins are known as their side effects including elevation in glucose levels, which is well documented as one of the risk factors for ischemic heart diseases. A number of investigations have shown that people on a high-dose regimen of the cholesterol drug atorvastatin and other cholesterol-lowering drugs may have a slightly increased risk of developing type 2 diabetes, particularly if they have several of the classic diabetes risk factors. Therefore, the American Heart Association (AHA) /The American College of Cardiology (ACC) stated separately the

This chapter will review *i)* at first, dyslipidemia as a risk factor for cardiovascular diseases, and then *ii)* the benefits and demerits for dyslipidemia treatments in type 2 diabetes using statins based on the data in several large cohort studies. *iii)* Furthermore, the discrepancy, statins can improve dyslipidemia but cannot prevent the new onset of type 2 diabetes, will be

**2.1. Dyslipidemia is one of the criteria of metabolic syndrome, pre-stage of type 2 diabetes** Prevalence of metabolic syndrome has been increasing with prevalence of obesity. The pathophysiology of metabolic syndrome is very complicated, but has been partially under‐ stood. It has been well documented metabolic syndrome is an important risk factor for cardiovascular diseases, especially heart diseases including heart failure and ischemic heart disease. Some studies have shown the prevalence of metabolic syndrome in the USA to be an estimated 34% of the adult population [15], and the prevalence increases with age. In addition, weight gain is associated with metabolic syndrome. Central obesity is the most important

guideline on dyslipidemia in 2013 [14].

**2. Statins in type 2 diabetes—Friends or Foe?**

discussed.

252 Treatment of Type 2 Diabetes

BMI, body mass index; EGIR, European Group of the study of Insulin Resistance; NCEP ATPIII, 3rd Recommendations of the Adult Treatment Panel of the National Cholesterol Education Program; HDL-cholesterol, high-density lipopro‐ tein cholesterol. Values in NECP definition and American Heart Association/Updated NCEP are approximations of values in mg/dL.

**Table 1.** Criteria for Metabolic Syndrome including Insulin Resistance (11)

In addition, many epidemiological and clinical studies have shown that insulin resistance may lead to dyslipidemia; Dyslipidemia, especially low HDL-cholesterol and high triglycerides are also important criteria with high glucose levels for the metabolic syndrome (Table 1). Carg [22] hypothesized approximately 20 years ago that insulin resistance might cause dyslipidemia in metabolic syndrome. Ruotolo and Howard [23] suggested that hyperinsulinemia as a com‐ pensatory mechanisms of insulin resistance leaded to, at first, very low-density of lipoprotein (VLDL) cholesterol overproduction, then the decreased clearance of fasting and postprandial triglyceride rich lipoproteins (TRLs), and the decreased production of HDL particles [23]. In addition, they suggested that increases in TRLs play major role in metabolic syndrome, and elevated VLDL-cholesterol and decreased HDL-cholesterol may be consequence of TRLs elevation. Very recently, the Framingham study [24] supported the close relationship between dyslipidemia and insulin resistance for the onset of coronary heart disease. The incidence of coronary heart disease risk associated with HDL-cholesterol or triglycerides were significantly increased only in the presence of insulin resistance.

#### **2.2. Dyslipidemia is an atherogenic factor**

It is well established that elevation of serum LDL is a major cause of atherosclerosis and coronary heart disease (CHD) [25-29]. Many epidemiological studies have shown that elevated LDL cholesterol level is strongly related to future cardiac events [30, 31]. Therefore, LDLcholesterol can be used as an important predictor for the future cardiac events in cardiac risk assessments (*i.e.* the Framingham Risk Score) [30, 31]. However, it is also known that other serum lipoproteins, such as triglyceride-rich lipoproteins (TRLs), very low-density lipopro‐ teins (VLDL), chylomicrons, and HDL-cholesterol, are involved. In atherogenic dyslipidemia, the pattern of lipoprotein abnormalities or atherogenic lipoprotein phenotype includes elevations of VLDL levels, increased small LDL particles, and low HDL-cholesterol [32, 33]. The abnormalities usually coexist because they have a common metabolic basis. Grundy summarized and figured the relationship insulin resistance, dyslipidemia and coronary heart disease [34]. Besides the multiple mechanisms for atherogenesis accompanying the lipid triad, atherogenic dyslipidemia commonly is associated with several non-lipid risk factors as part of metabolic syndrome (insulin resistance) [35]. In addition, the prothrombotic state may be accompanied by several abnormalities in the coagulation system in metabolic syndrome; most notable are elevations in fibrinogen and plasminogen activator inhibitor-1 (PAI-1). These phenomena might be related to the onset and development of atherogenic damage in vessels

#### **2.3. Statins can improve dyslipidemia in type 2 diabetes, and result in the prevention for coronary heart diseases or other cardiovascular events.**

A number of large cohort clinical studies on the efficacy of statins, especially atorvastatin, have been conducted for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). [36, 37] In primary prevention, CARDS (Collaborative Atorvastatin Diabetes Study) [38] showed that atorvastatin 10 mg/day signifi‐ cantly reduced cardiovascular events compared to placebo (relative risk of the composite primary endpoint; acute CHD events, coronary revascularisation, or stroke) by 37% (p = 0.001). The decrease of cardiovascular events in CARDS study with atorvastatin was similar to those in the ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm) with atorvastatin [39, 40] and HPS (Heart Protection Study) with simvastatin [41]. However, lipids lowering effects of atorvastatin was observed to be faster compared to simvastatin, 6 months with atorvastatin observed in CARDS [38] versus 15-18 months in simvastatin observed in HPS [41]. The ASCOT-LLA trial [39] conducted in 2,226 hypertensive diabetic patients without previous cardiovascular disease, showed that atorvastatin could decrease the relative risk on primary coronary heart diseases (CHD) by 36% (p=0.0005), and all cardiovascular diseases (CVD) risk by 25% (p = 0.038) compared to placebo. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) [42, 43] and TNT (Treating to New Targets) trials [44, 45] demonstrate that both low (10 mg/day) and high (80 mg/day) doses of atorvastatin reduced the risk of non-fatal myocardial infarction by 17-22% (p < 0.02). [42-45]

In addition, many epidemiological and clinical studies have shown that insulin resistance may lead to dyslipidemia; Dyslipidemia, especially low HDL-cholesterol and high triglycerides are also important criteria with high glucose levels for the metabolic syndrome (Table 1). Carg [22] hypothesized approximately 20 years ago that insulin resistance might cause dyslipidemia in metabolic syndrome. Ruotolo and Howard [23] suggested that hyperinsulinemia as a com‐ pensatory mechanisms of insulin resistance leaded to, at first, very low-density of lipoprotein (VLDL) cholesterol overproduction, then the decreased clearance of fasting and postprandial triglyceride rich lipoproteins (TRLs), and the decreased production of HDL particles [23]. In addition, they suggested that increases in TRLs play major role in metabolic syndrome, and elevated VLDL-cholesterol and decreased HDL-cholesterol may be consequence of TRLs elevation. Very recently, the Framingham study [24] supported the close relationship between dyslipidemia and insulin resistance for the onset of coronary heart disease. The incidence of coronary heart disease risk associated with HDL-cholesterol or triglycerides were significantly

It is well established that elevation of serum LDL is a major cause of atherosclerosis and coronary heart disease (CHD) [25-29]. Many epidemiological studies have shown that elevated LDL cholesterol level is strongly related to future cardiac events [30, 31]. Therefore, LDLcholesterol can be used as an important predictor for the future cardiac events in cardiac risk assessments (*i.e.* the Framingham Risk Score) [30, 31]. However, it is also known that other serum lipoproteins, such as triglyceride-rich lipoproteins (TRLs), very low-density lipopro‐ teins (VLDL), chylomicrons, and HDL-cholesterol, are involved. In atherogenic dyslipidemia, the pattern of lipoprotein abnormalities or atherogenic lipoprotein phenotype includes elevations of VLDL levels, increased small LDL particles, and low HDL-cholesterol [32, 33]. The abnormalities usually coexist because they have a common metabolic basis. Grundy summarized and figured the relationship insulin resistance, dyslipidemia and coronary heart disease [34]. Besides the multiple mechanisms for atherogenesis accompanying the lipid triad, atherogenic dyslipidemia commonly is associated with several non-lipid risk factors as part of metabolic syndrome (insulin resistance) [35]. In addition, the prothrombotic state may be accompanied by several abnormalities in the coagulation system in metabolic syndrome; most notable are elevations in fibrinogen and plasminogen activator inhibitor-1 (PAI-1). These phenomena might be related to the onset and development of atherogenic damage in vessels

**2.3. Statins can improve dyslipidemia in type 2 diabetes, and result in the prevention for**

A number of large cohort clinical studies on the efficacy of statins, especially atorvastatin, have been conducted for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). [36, 37] In primary prevention, CARDS (Collaborative Atorvastatin Diabetes Study) [38] showed that atorvastatin 10 mg/day signifi‐ cantly reduced cardiovascular events compared to placebo (relative risk of the composite primary endpoint; acute CHD events, coronary revascularisation, or stroke) by 37% (p = 0.001).

increased only in the presence of insulin resistance.

**coronary heart diseases or other cardiovascular events.**

**2.2. Dyslipidemia is an atherogenic factor**

254 Treatment of Type 2 Diabetes

Sub-studies of the GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) [45-48], TNT (Treating to New Targets) [43, 49-51] and PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) [52-54] trials showed similar results of atorvastatin reduced cardiac events but not only patients without diabetes but also in those with diabetes. Those studies included 15-25% of patients with diabetes.

In the GREACE sub-study, which compared to physicians'standard care [47], atorvastatin significantly reduced the relative risk of total mortality and cardiac moratility and morbidity (coronary mortality, coronary morbidity, and stroke). Furthermore, atorvastatin improved renal function [47] and liver function [46]. Of interest, patients with non-alcoholic fatty liver disease, statins (atorvastatin 24 mg/day) improved liver function, although liver injury was worsen in others without statin treatment for dyslipidemia. This study demonstrated that statin treatment is safe for mild-to-moderate liver injury caused by non-fatty liver disease, and can improve liver injury and reduce cardiovascular morbidity. In addition, statins treatment has benefits for all age groups including old patients. In the older patients, intensive lipids lowering treatments are more effective to reduce cardiovascular risks compared to younger patients when compared to usual lipids lowering treatment. The GREACE study demonstrated that one should not deprive older patients of CVD prevention treatment and lipid target achievement. [48]

Similarly, TNT (Treating to New Targets) trials [49, 50] demonstrate the preventive efficacy of atorvastatin on the reductions of cardiac events in patients with stable CHD. In the TNT substudy [51] including a total of 9,251 coronary heart disease patients with low-density lipopro‐ tein cholesterol, higher dose of atorvastatin (80 mg/day) over 4.9 years was more effective on the prevention on major cardiovascular events (n=729) such as coronary death, non-fatal myocardial infarction, cardiac arrest, or stroke regardless of fatal or non-fatal, compared to lower dose (10 mg/day). [52] In sub-analysis of TNT trial conducted in 5,584 CHD patients with metabolic syndrome, higher dose of atorvastatin (80mg/day) reduced the major cardio‐ vascular and cerevrovascular events by 29%. In addition, this sub-study also demonstrated that CHD patients with metabolic syndrome had a 44% greater level of absolute cardiovascular risk compared to those without metabolic syndrome, indicating the clinical feasibility of administering intensive lipid-lowering therapy to CHD patients with metabolic syndrome [53]. In addition, the other sub-analysis [43] demonstrated even in treatment resistant hyper‐ tensive patients, who were at high risk of cardiac events, intensive lipid lowering with atorvastatin 80 mg is associated with a significant reduction in cardiovascular events.

In the PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) sub-study [54, 55], a significantly lower incidence of acute cardiac events was reported in patients with atorvastatin compared to pravastatin (21.1% vs. 26.6%; p = 0.03). Therefore, an absolute risk reduction of 5.5% was associated with atorvastatin therapy [54-56]. Similarly, the IDEAL trial (the Incremental Decrease in End Points through Aggressive Lipid Lowering trial) [57] compared the effects on cardiovascular risks between atorvastatin 80 mg daily versus sim‐ vastatin 20-40 mg daily in post-myocardial infarction patients. The IDEAL trial had smaller statistical power due to the smaller number of patients compared to the PROVE-IT study, but longer follow-up (5 years vs. 2 years). Interestingly, decreases in the relative risk of cardio‐ vascular events at 5 years in group with simvastatin was similar to that in the 2-year followup with atorvastatin group, and the decreases in the cardiovascular risk maintained consistently from 2 years to 5 years in atorvastatin group. The 2 treatment regimens (atorvas‐ tatin versus simvastatin) were well tolerated. These results indicated that patients with recent myocardial infarction should be on intensive statin therapy with atorvastatin and maintain the high dose of atorvastatin as long as possible, over 2 years.

ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in Noninsulin-dependent diabetes mellitus) [58] in 2,410 type 2 diabetic patients demonstrated that a 29% lower low-density lipoprotein-cholesterol level was seen with atorvastatin than placebo at endpoint (p < 0.0001) over a 4-year period. In sub-analysis in the 505 subjects with prior myocardial infarction or interventional procedure, atorvastatin did not reduce relative risk of a primary end-point (cardiovascular mortality, non-fatal major cardiovascular event, stroke, and unstable angina pectoris, fatal or non-fatal myocardial infaction). Therefore, ASPEN trial failed to confirm the benefit of atorvastatin on cardiocvascular risk in type 2 diabetes [58].

The ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) [59-61] and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) [62, 63] trials demonstrated the benefits of treatment with atorvastatin for dyslipidemia compared to usual care with generic statins as the real practical clinic (*i.e.* simvastatin) in patients with stable CHD. Atorvastatin reduced the risk of non-fatal myocardial infarction by 47-59% (p < 0.0002) compared to usual dyslipidemia therapy with generic statins as a usual community practice in 2008. The MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) [64, 65], PROVE-IT [54] and IDEAL-ACS (Acute Coronary Syndromes) [57] studies also recommend the benefits of high-dosage atorvastatin therapy started from early phase after the onset of acute coronary syndrome such as within 24-96 hours observed in the MIRACL trial. When compared to placebo, all statins including pravastatin and simvastatin, atorvastatin are effective to reduce the risk of death or major cardiovascular events by 16-18% (p = 0.048). In patients undergoing revascularization procedures, the AVERT (Atorvastatin VErsus Revas‐ cularization Treatment) study [66] revealed that administration of atorvastatin 80 mg/day over 18 months had similar benefits on reducing the ischemic cardiac risk to angioplastity plus usual care in low-risk patients with stable coronary artery disease. Furthermore, Arca [62] reviewed that the ARMYDA (Atorvastatin for Reduction in MYocardial DAmage during angioplasty) and ARMYDA-3 trials showed atorvastatin's benefits on myocardial infaction patients; Atorvastatin 40 mg/day over 7 days before coronary intervention significantly reduced the risks of myocardial ischemic damage (ARMYDA), post-procedural acute myocardial infarc‐ tion (ARMYDA) and atrial fibrillation (ARMYDA-3) versus placebo. In addition, it has been observed that post-myocardial infactionm patients without atorvastatin have significantly higher C-reactive protein levels and higher prevalence of the combined incidence of cardio‐ vascular events (death, MI and target segment revascularization during the 6-month followup). In addition, the ATTEMP study (Assessing The Treatment Effect in Metabolic syndrome without Perceptible diabetes) [67] showed atorvastatin improved renal function and reduced serum uric acid levels in metabolic syndrome without cardiovascular diseases. These changes were more prominent in stage 3 chronic kidney diseases patients and might have contributed to the reduction in cardiovascular risk and clinical events.

Overall, therefore, the marked efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events were provided in many large cohort trials not only in relative healthy individuals, but also in diabetes or post-myocardial infarction patients, and the effects were stronger than usual statins such as simvastatin. Atorvastatin has in general cardiovascular disease management including improving renal function, and liver injury with non-alcoholic fatty liver, suggests even greater potential clinical utility for the drug in some clinical settings. [37, 66] The results from the meta-analysis using 31 randomized studies compared statins and placebo or other statins showed in patients with CVD, (or at risk of CVD), statin reduced relative risk of all cause mortality, cardiovascular mortality, coronary heart disease mortality and fatal myocardial infarction, but did not reduce the risk of fatal stroke. Statin could not reduce relative risk of morbidity of non-fatal stroke, non-fatal myocardial infarction, transient ischemic attack (TIA), unstable angina, and coronary revascularization.

The differentiations on the clinical efficacy between statins; atorvastatin, fluvastatin, pravas‐ tatin and simvastatin, are almost impossible from the previous large clinical studies, however, there is some evidence from direct comparisons between statins to suggest that atorvastatin may be more effective than pravastatin in patients with symptomatic coronary heart diseases, although there is limited evidence for the effectiveness of statins in different subgroups [67].

#### **2.4. Statins may improve renal function**

[53]. In addition, the other sub-analysis [43] demonstrated even in treatment resistant hyper‐ tensive patients, who were at high risk of cardiac events, intensive lipid lowering with

In the PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) sub-study [54, 55], a significantly lower incidence of acute cardiac events was reported in patients with atorvastatin compared to pravastatin (21.1% vs. 26.6%; p = 0.03). Therefore, an absolute risk reduction of 5.5% was associated with atorvastatin therapy [54-56]. Similarly, the IDEAL trial (the Incremental Decrease in End Points through Aggressive Lipid Lowering trial) [57] compared the effects on cardiovascular risks between atorvastatin 80 mg daily versus sim‐ vastatin 20-40 mg daily in post-myocardial infarction patients. The IDEAL trial had smaller statistical power due to the smaller number of patients compared to the PROVE-IT study, but longer follow-up (5 years vs. 2 years). Interestingly, decreases in the relative risk of cardio‐ vascular events at 5 years in group with simvastatin was similar to that in the 2-year followup with atorvastatin group, and the decreases in the cardiovascular risk maintained consistently from 2 years to 5 years in atorvastatin group. The 2 treatment regimens (atorvas‐ tatin versus simvastatin) were well tolerated. These results indicated that patients with recent myocardial infarction should be on intensive statin therapy with atorvastatin and maintain

ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in Noninsulin-dependent diabetes mellitus) [58] in 2,410 type 2 diabetic patients demonstrated that a 29% lower low-density lipoprotein-cholesterol level was seen with atorvastatin than placebo at endpoint (p < 0.0001) over a 4-year period. In sub-analysis in the 505 subjects with prior myocardial infarction or interventional procedure, atorvastatin did not reduce relative risk of a primary end-point (cardiovascular mortality, non-fatal major cardiovascular event, stroke, and unstable angina pectoris, fatal or non-fatal myocardial infaction). Therefore, ASPEN trial failed to confirm the benefit of atorvastatin on cardiocvascular risk in type 2 diabetes [58].

The ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) [59-61] and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) [62, 63] trials demonstrated the benefits of treatment with atorvastatin for dyslipidemia compared to usual care with generic statins as the real practical clinic (*i.e.* simvastatin) in patients with stable CHD. Atorvastatin reduced the risk of non-fatal myocardial infarction by 47-59% (p < 0.0002) compared to usual dyslipidemia therapy with generic statins as a usual community practice in 2008. The MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) [64, 65], PROVE-IT [54] and IDEAL-ACS (Acute Coronary Syndromes) [57] studies also recommend the benefits of high-dosage atorvastatin therapy started from early phase after the onset of acute coronary syndrome such as within 24-96 hours observed in the MIRACL trial. When compared to placebo, all statins including pravastatin and simvastatin, atorvastatin are effective to reduce the risk of death or major cardiovascular events by 16-18% (p = 0.048). In patients undergoing revascularization procedures, the AVERT (Atorvastatin VErsus Revas‐ cularization Treatment) study [66] revealed that administration of atorvastatin 80 mg/day over 18 months had similar benefits on reducing the ischemic cardiac risk to angioplastity plus usual care in low-risk patients with stable coronary artery disease. Furthermore, Arca [62] reviewed

atorvastatin 80 mg is associated with a significant reduction in cardiovascular events.

the high dose of atorvastatin as long as possible, over 2 years.

256 Treatment of Type 2 Diabetes

The comparisons analysis related to renal function [43] from clinical trials with data from 149,882 patient-years of follow-up failed to show an association between high-potency statins and risk of acute kidney injury with statins (10,345 patients on atorvastation, 10-80 mg/day) compared with controls (placebo, 8,945 patients with placebo). In addition, there were no differences in effects on renal function between high-dose versus low-dose. This comparison was performed in the 24 placebo-controlled trials including IDEAL [57], TNT [47], CARDS [69, 70], ASPEN (The Atorvastatin Study for Prevention of coronary heart disease Endopoints in Non-diabeties mellitus) [58], SPARCL (The Stroke Prevention by Aggressive Reduction in Cholesterol Levels) [43, 71], and other large study using placebo with 10,345 patients with atorvastatin and 8945 patients with placebo. [43]

The TNT trial in 10,001 CHD patients with and without pre-existing chronic kidney diseases demonstrated efficacy of atorvastatin (80 mg/day) on reduction of CHD risk as well as improving renal function in both with and without pre-existing renal injury patients. No difference in the incidence of renal-related serious adverse events were observed at 120 days (0.04% in atorvastatin; 0.10% in placebo, p = 0.162) [50, 51]. Similarly, the use of a high-potency statin regimen did not increase the risk of kidney injury was observed in 2 large randomized trials of statin therapy in patients with acute coronary syndrome; PROVE IT-TIMI 22 [50, 55] (atorvastatin 80 mg/day) including 4,162 patients, and A-to-Z trial (pravastatin 40 mg/day for 1 month + simvastatin 80 mg/day after 1 month) including 4, 497 patients. [72] As mentioned in the previous section, the ATTEMP (Assessing the treatment Effect in Metabolic syndrome without Perceptible diabetes) study [67] showed that multifactorial intervention in patients with metabolic syndrome without established CVD improved renal function and reduced serum uric acid levels. Of importance, these changes were more prominent in stage 3 chronic kidney diseases patients. PROVE-IT-TIMI 22 sub-study [73] used urinary albumin excretion as an index of renal injury, showed no significant change in urinary albumin concentration from enrollment to end of study in either the standard (pravastatin 40 mg/day) or intensive (atorvastatin 80 mg/day) statin therapy groups in an acute coronary syndrome in statin treated patient. [52] Microalbuminuria may reflect traditional cardiovascular risk factor burden and offer little prognostic information independent of those factors. [52]

#### **2.5. Cost-effectiveness**

Cost-effectiveness between statins has been compared in several studies such as the Aggressive Lipid-lowering Initiation Abates New Cardiac Events study (ALLIANCE study) [73], and those observations showed the advantage of atorvastatin in high-risk CVD patients [68] and type 2 diabetes patients [74]. Despite the non-adherence levels observed in actual practice, statin treatment is cost-effective for primary prevention in patients newly diagnosed with type 2 diabetes. Because of large differences in cost-effectiveness according to different risk and age groups, the efficiency of the treatment could be increased by targeting patients with relatively higher cardiovascular risk and higher ages [74]. When the efficacy and cost-effectiveness were compared between rosuvastatin, atorvastatin, pravastatin and simvastatin, rosuvastatin therapy in commonly prescribed doses is most effective for improving hypercholesterolemia and most cost effective in diabetic patients with and without metabolic syndrome. [75] The PROVE IT trial [76] demonstrated that atorvastatin 80 mg/day has stronger efficacy on reducing cardiovascular events compared to pravastatin 40 mg/day in patients with acute coronary syndrome. Genetic investigations in PROVE-IT sub-study showed that the preva‐ lence of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in non-carriers. Parthan *et al.* [76] assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients, and they found that cost-effectiveness is sensitive to the price of generic atorvastatin and the effect on adherence of knowing KIF6 carrier status.

#### **2.6. The JUPITER trial and meta-analyses show statins increase the risk of new onset of type 2 diabetes**

The TNT trial in 10,001 CHD patients with and without pre-existing chronic kidney diseases demonstrated efficacy of atorvastatin (80 mg/day) on reduction of CHD risk as well as improving renal function in both with and without pre-existing renal injury patients. No difference in the incidence of renal-related serious adverse events were observed at 120 days (0.04% in atorvastatin; 0.10% in placebo, p = 0.162) [50, 51]. Similarly, the use of a high-potency statin regimen did not increase the risk of kidney injury was observed in 2 large randomized trials of statin therapy in patients with acute coronary syndrome; PROVE IT-TIMI 22 [50, 55] (atorvastatin 80 mg/day) including 4,162 patients, and A-to-Z trial (pravastatin 40 mg/day for 1 month + simvastatin 80 mg/day after 1 month) including 4, 497 patients. [72] As mentioned in the previous section, the ATTEMP (Assessing the treatment Effect in Metabolic syndrome without Perceptible diabetes) study [67] showed that multifactorial intervention in patients with metabolic syndrome without established CVD improved renal function and reduced serum uric acid levels. Of importance, these changes were more prominent in stage 3 chronic kidney diseases patients. PROVE-IT-TIMI 22 sub-study [73] used urinary albumin excretion as an index of renal injury, showed no significant change in urinary albumin concentration from enrollment to end of study in either the standard (pravastatin 40 mg/day) or intensive (atorvastatin 80 mg/day) statin therapy groups in an acute coronary syndrome in statin treated patient. [52] Microalbuminuria may reflect traditional cardiovascular risk factor burden and

Cost-effectiveness between statins has been compared in several studies such as the Aggressive Lipid-lowering Initiation Abates New Cardiac Events study (ALLIANCE study) [73], and those observations showed the advantage of atorvastatin in high-risk CVD patients [68] and type 2 diabetes patients [74]. Despite the non-adherence levels observed in actual practice, statin treatment is cost-effective for primary prevention in patients newly diagnosed with type 2 diabetes. Because of large differences in cost-effectiveness according to different risk and age groups, the efficiency of the treatment could be increased by targeting patients with relatively higher cardiovascular risk and higher ages [74]. When the efficacy and cost-effectiveness were compared between rosuvastatin, atorvastatin, pravastatin and simvastatin, rosuvastatin therapy in commonly prescribed doses is most effective for improving hypercholesterolemia and most cost effective in diabetic patients with and without metabolic syndrome. [75] The PROVE IT trial [76] demonstrated that atorvastatin 80 mg/day has stronger efficacy on reducing cardiovascular events compared to pravastatin 40 mg/day in patients with acute coronary syndrome. Genetic investigations in PROVE-IT sub-study showed that the preva‐ lence of event reduction was greater in carriers of the Trp719Arg variant in kinesin family member 6 protein (KIF6) than in non-carriers. Parthan *et al.* [76] assessed the cost effectiveness of testing for the KIF6 variant followed by targeted statin therapy (KIF6 Testing) versus not testing patients, and they found that cost-effectiveness is sensitive to the price of generic

offer little prognostic information independent of those factors. [52]

atorvastatin and the effect on adherence of knowing KIF6 carrier status.

**2.5. Cost-effectiveness**

258 Treatment of Type 2 Diabetes

Statins are known as well-tolerated and very rare adverse events reported. Side effects of statins are very rare but still exist such as elevations of liver enzymes, muscle aches, and very rarely, rhabdomyolysis [76]. If people have adverse events, discontinuation is primary as usual procedure to resolve these adverse events similarly to other any medications.. Recently, debate has focused on the possible negative long-term effects of statin treatment on cognitive decline, and the incidence of cancer [78]. Some investigators have documented that statins affect the risk of developing cancer, when they are taken at low doses for managing hypercholestero‐ laemia. There is some possibility of an increased cancer risk in elderly patients associated with hydrophilic statin use. On the other hand, some recent studies have shown the benefits of statins in modifying the prognosis of cancer, and the decreases in the risks of certain cancers, such as gastric, oesophageal, liver, colorectal and advanced/aggressive prostate cancer. In addition, Jukema *et al.* [78] reported that there was no increased risk of cognitive decline or cancer with statin use. However, regarding the relations between statins and cancer, results remain controversial. Further investigations will be necessary to clarify.

Since the report of the new onset of diabetes during rosuvastatin treatment, as an unexpected finding in the JUPITER trial [7], safety concerns on abnormal glucose metabolisms related to statins have emerged in 2012. The possible association of diabetes with statin therapy has been discussed over several years, but statins' effects on reducing of cardiovasculoar risk has been overweighted than the new onset of diabetes or glucose metabolism impairement. In addition, guidelines of the American Diabetes Association [3], American Heart Association [1, 14], and American Copllege of Cardiology [14] have shown the same direction of overweighting on dyslipidemia control. In addition, several studies and meta-analysis data have shown that statin use is related to a small increased risk of type 2 diabetes mellitus. The JUPITER (Justifi‐ cation for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial [79-81] demonstrated new onset of diabetes, although rosuvastatin reduces cardiovascular events and all-cause mortality and concomitant evidence of moderate chronic kidney diseases. The JUPITER finding on impairement of glucose metabolisms was the first data showing the strong relationship between statins and the new onset of diabetes. The JUPITER trial [78, 80]was conducted in 17,603 men and women without histories of cardiovascular diseases or diabetes with randomized, double blind design to evaluate the efficacy of rosuvastatin 20 mg/ day over 5 years. In this trial, the participants who had diabetes risk factor (n=11,508), showed developing diabetes more frequently than those without a diabetic risk factor (n=6,095). In individuals with diabetic risk factors, rosuvastatin decreased the cardiovascular risks such as the primary endpoint by 39%, venous thrombosis by 36%, and total mortality by 17%, but increased diabetes risk by 28 %. On the other hand, in the participants without diabetic risk factors, all parameters decreased significantly with larger drops compare dto those with diabetic risk factors (primary endpoint by 52%; venous thrombosis by 53%; total mortality by 22 %). And, importantly, no elevations in the new onset of diabetes or impairment of glucose metabolism were observed. These results suggested that statins may have more stronger benefits on reduction of cardiovascular risks and glucose metabolisms in individuals without diabetes compared to those with diabetes. When compared to placebo, the onset of diabetes needed longer duration by 5,4 weeks in rosuvastatin (rosuvastatin, 84.3 weeks vs placebo, 89.7 weeks). The benefits on cardiovascular risk and total mortality in rosuvastatin group were greater than the hazard of the new onset of diabetes [7].

Furthermore, three recent meta-analyses of large-scale placebo-controlled and standard carecontrolled trials [82] showed approximately more than 10% increased risk for incident diabetes associated with statin therapy. [83, 84]

On the other, recently the post hoc analysis of ATTEMPT study assesses the incidence of newonset diabetes over 3.5 years in patients with metabolic syndrome observed no differences in the new onset of diabetes in patients with statins (statins, 0.83 vs. placebo, 1.00/100 patientyears) from the general population [67, 85], and no differences in the new onset of diabetes between individuals with and without diabetic risk factors [84]. New-onset diabetes incidence and CVD events were negligible and not different from what is expected in the general population. [85]

Park *et al.* [9] analysed the linkage of statins and the new-onset diabetes using meta-analysis in published large cohort studies in MEDLINE from 2000 to October 2013 with the following MESH terms and text key words alone or in combination were included: 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors, HMG-CoA reductase inhibitors, statins, incident diabetes, new-onset diabetes, insulin resistance, impaired insulin secretion, metaanalysis, cohort study, and observational study written in English. Results of observational studies and meta-analyses show association of incident diabetes with statin use in patients with concomitant risk factors for diabetes. They concluded a possible association between statin use and incident diabetes in patients with underlying diabetes risk factors in available clinical data. Although study data may be insufficient to change the current practice paradigm, clinicians should vigilantly monitor for incident diabetes in patients on statins. Patients with a low risk of CVD and high risk of diabetes should reconsider statin use and focus on lifestyle management. Each statins has different effects on glucose metabolisms, and women and elderly persons are known at higher risk of diabetes. Therefore, various confounders related to adverse events, especially glucose metabolisms, should be considered

Muscoqiuri, *et al.* [86] discussed the effects of statins on insulin sensitivity or insulin secretion, because statins deteriorates glycemic control may accelerate progression to diabetes via molecular mechanisms that impact insulin sensitivity and secretion. The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, but basic science studies could not find a clear molecular explanation from searches of computerized databases, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity.

A number of meta-analyses conducted in recent years have demonstrated that the association is real but causality has not yet been proved [8]. And the underlying mechanisms for this association remain unclear.

In summary, although many clinical studies have demonstrated that statins worsen glucose metabolism or cause the new onset of diabetes, the cardiovascular benefits of statin therapy overweigh the risk of impairment of glucose metabolism. Clinical practice for statin therapy should not be changed on the basis of the most recent Food and Drug Administration infor‐ mational warnings in 2012. Therefore, the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control.


**3. Intra-operative and immediate post-operative considerations**

Although surgical and anaesthetic approaches and considerations are outside the scope of this chapter, intra-operative events have significant impacts on patient and graft outcomes. Review and documentation of intra-operative and immediate postoperative factors can help predict and guide subsequent clinical course (**Table 5**).

Any surgical complications or anatomical challenges (notably presence of multiple renal arteries, difficult bench surgery and renal capsule tear) should be communicated by the transplant surgeons as these can help predict perioperative complications. If available, intraoperative Doppler assessments should be documented to confirm adequate post-perfusion flow parameters in the transplanted kidney. Where there is perioperative concern regarding allograft perfusion, or early unexpected oligoanuria, an early duplex ultrasound may be requested to confirm flow in the transplant vessels.

Significant blood loss, requirement of inotropic support and intra-operative haemodynamic instability indicate suboptimal organ perfusion and are risk factors for delayed graft function (Section 5.4). Central venous line is placed at the time of surgery, and central venous pressure (CVP) is still used intra-operatively and in the immediate post-operative period. It is important to acknowledge controversies in absolute CVP targets, with studies advocating improved outcomes with high CVP (10–15 mmHg) targets at reperfusion [40, 41] and others observing increased kidney dysfunction with CVP >11 mmHg [42]. In general, intra-operative CVP trends can inform fluid management, but should not form the basis of a fluid management strategy due to inconsistent correlation with intravascular volumes [43].

Despite preoperative optimization, hyperkalaemia is common post-operatively due to tissue trauma and resorption of intra-abdominal blood. The presence of

#### **Table 5.** *Post-operative documentation.*

hyperkalaemia >6 mmol/L in the immediate post-operative period should prompt consideration of dialysis depending on the urine output. If graft urine output (with native residual renal function deducted) is >100 mL/h, it may be reasonable to manage the patient medically with insulin-dextrose infusion and loop diuretics. It should also be noted that intraoperative use of insulin-dextrose often results in rebound hyperkalaemia postoperatively.

#### **4. Perioperative fluid management**

Optimal fluid management strategy is contentious, although there is good evidence that fluid loading to maintain cardiac output and optimise renal perfusion, improves outcomes [44]. Intra-operative blood losses and fluid balance can be estimated through discussion with the transplant surgeon and anaesthetist and review of anaesthetic chart (Section 3). Currently, no studies on fluid management in the perioperative phase of renal transplantation exist to guide practice. A recent randomised trial demonstrated non-inferiority of a non-restrictive perioperative intravenous fluid strategy in high-risk abdominal surgery in terms of disability-free survival. Furthermore, the restrictive fluid strategy was associated with increased rates of acute kidney injury (8.6 vs. 5.0%. p < 0.001) [45]. Although generalizability to renal transplantation is uncertain, a restrictive fluid strategy should be avoided.

A common strategy for managing post-operative fluid replacement in the hours after kidney transplantation is to replace the urine output from the previous hour plus 30 mL to account for insensible losses. A loop diuretic and/or mannitol is sometimes administered during the transplant surgery to precipitate a diuresis, decreasing requirement for dialysis, but has not been shown to improve graft outcomes [46].

Frequent clinical assessment of the recipient's fluid status, including the jugular venous pressure, heart rate, blood pressure and urine output, is important to ensure adequate fluid replacement and to avoid volume overload. Traditional parameters and clinical assessment of fluid status, however, may be unreliable due to compromised homeostatic mechanisms in ESKD and the post-ischaemic transplanted kidney [47]. As soon as it is feasible post-transplant, recipients should be weighed with comparison to their preoperative weight as an objective guide to fluid status.

There is currently no evidence supporting one type of intravenous fluid therapy over another, although a pragmatic, registry-based, multi-centre, doubleblind, randomised controlled trial comparing balanced crystalloid solution (PlasmaLyte) with 0.9% saline on the incidence of delayed graft function in 800 adults and children with end-stage kidney disease (ESKD) receiving a deceased donor kidney transplant in Australia and New Zealand is currently underway (ACTRN12617000358347).

A good urine output in the early post-transplant period is a helpful indicator of early graft function, although it may not be possible to differentiate allograft urine output from native urine output in recipients who have significant residual renal function. Oligoanuria may be an indicator of delayed graft function or a harbinger of an early complication, especially if the urine output was good initially (Section 5.4). An urgent ultrasound is a useful investigation to assess perfusion of the allograft at the bedside and to check for evidence of ureteric or vascular complications. The presence of hypoechoic fluid collections may indicate haemorrhage or urinary anastomotic leak (Section 5).

Blood tests to monitor serum creatinine and electrolytes are collected immediately post-transplant and then 6–12 h to monitor renal function and exclude

**19**

**Table 6.**

Blood tests:

Alternate day CNI levels

Post-operative chest radiograph

*Common post-operative surveillance investigations.*

*Perioperative Care for Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.84388*

**5. Early complications**

tions (**Table 6**).

hyperkalaemia. Some recipients may develop a significant diuresis, passing over a litre of urine per hour, and in this situation, frequent monitoring of blood tests 4–6

Complications in the perioperative phase are diverse, reflecting pre-existing transplant recipient comorbidities as well as individual surgical challenges. With the potential for there to be few symptoms from the denervated graft, most centres follow a protocol of investigations for early identification of post-transplant complica-

Generally, an early renal transplant duplex ultrasound can identify vascular or anastomotic complications including renal vessel thrombosis or compression. The resistive index (RI) (measured peak systolic velocity—end diastolic velocity/ peak systolic velocity), normally, between 0.60 and 0.80, with levels >0.8 suggesting abnormal perfusion of the allograft, is a widely reported measure of allograft perfusion for duplex scans but does not seem to correlate well with renal histology [48]. A positive correlation has been reported between RI and recipient mortality, and the strongest predictor of an elevated RI was recipient age, suggesting that RI may be an indicator of recipient vascular disease [48]. Consequently, although the

Similarly, nuclear medicine imaging, such as a mercaptoacetyltriglycine (MAG3) or diethylenetriamine pentaacetic acid (DTPA) renogram, can assist in the assessment of allograft perfusion and early graft function as well as identify a ureteric anastomotic leak. Radionucleotide scanning may give an indication of the likely

Electrolyte abnormalities are a frequent occurrence in the early post-transplant

period. Perioperative hyperkalaemia is often followed by hypokalaemia due to diuretics and polyuria combined with large volume IV fluid replacement. Hypomagnesaemia is exacerbated by the tubular effects of CNI therapy and is associated with an increased risk of post-transplant diabetes [51, 52]. Hypophosphatemia is almost universal as a consequence of elevated FGF23 and PTH levels [53, 54]. To reduce the chance of arrhythmias, intravenous electrolyte replacement should target potassium levels in the normal range (3.5–5 mmol/L) and a serum magnesium >0.4 mmol/L. Hypophosphatemia is not usually associated with adverse clinical sequelae, but if severe (<0.4 mmol/L) can also be managed with intravenous replacement. Many transplant recipients require ongoing oral replacement of potassium, magnesium and occasionally phosphate in the first few weeks post-transplant,

RI is commonly reported, clinicians need to be aware of its limitations.

**5.1 Haematological, biochemical and metabolic derangement**

although this may be limited by gastrointestinal adverse effects.

Daily capillary glucose levels—if abnormal, manage as diabetes mellitus

Twice daily full blood count and serum biochemistry

Duplex ultrasound imaging, usually at days 2–4 post-transplant MAG3/DTPA renogram as indicated by clinical progress

duration of delayed graft function [49, 50].

h is recommended to avoid over or under replacement of electrolytes.

hyperkalaemia. Some recipients may develop a significant diuresis, passing over a litre of urine per hour, and in this situation, frequent monitoring of blood tests 4–6 h is recommended to avoid over or under replacement of electrolytes.


**Acknowledgements**

Laboratory of Bioengineering and Tissue Regeneration-University of Málaga (LABRET-UMA) is supported by grants from the Spanish (PI10/02529, and Red de Terapia Celular, RD06/00100014), and the Andalusian Governments (PI-0729-2010, and PAID BIO217). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, *Iniciativa Ingenio 2010, Consolider Program, CIBER Actions* and financed by the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) with assistance from the *European Regional Development Fund.*

This chapter has been designed, coordinated and written by Professor José A. Andrades and some of his students, in a novel educational initiative at the University of Málaga (Spain), academic course 2011/12.


**2. Healthy pregnancy** *vs***. lupus pregnancy**

It is critical to mention that pregnancy represents a unique clinical situation, physiologically characterized by a well-documented Th2-cell polarization at both systemic and maternal-fetal interfaces, developed on a background of depressed cellular-mediated immunity, changes in Th1/Th2 cytokine profile, and placental synthesis of complement inhibitors [4, 9, 10]. Also, progressively increased levels of sex hormones - estrogens, progesterone, prolactin, as well as and glucocorticoids are commonly reported during pregnancy [1, 4, 9, 10]. Complex immunological and hormonal adaptive mechanisms are activated to allow the tolerance of fetus classically considered as an immunogenic allograft [4, 9].

A closer look to the pathogenic pathways of autoimmune rheumatic conditions emphasizes specific genetic susceptibility and aberrant immune response driving definite behavior during pregnancy [4, 10]. Rheumatic diseases respond differently to pregnancy, as immune system adjustments may positively or negatively interrelate with underlying autoimmune disease: spontaneous improvement occurs in some of them, while persistent activity or severe flares are seen in others, such as systemic lupus erythematosus [1, 4, 10].

Despite significant progress in understanding and treating autoimmune rheumatic conditions, pregnancy in such patients remains a challenge due to complex interplay between pregnancy, disease activity and medication; the main debate focuses on the paradigm "flare without medication" *vs*. "safe drug in pregnancy", emerging the unmet needs for pregnant rheumatic patients [1, 4, 6, 9, 10].

Furthermore, it is widely recognized that the management of reproductive issues in patients with rheumatic diseases commonly differs from general population, requiring a cross-over team with rheumatologists, specialists in the fields of obstetrics-gynecology and maternal-fetal medicine, and, in special cases, reproductive endocrinology and infertility [1–4, 10]. Patients should be counseled about contraception, pregnancy and lactation; additionally, pregnancy in IMRDs needs to be planned and risks assessed in mother and child [1–4, 10, 11]. High-risk pregnancies require careful monitoring and tailored therapy to secure maternal health and positive pregnancy outcomes [4, 10].

Systemic lupus erythematosus is a multi-system autoimmune disease of still unknown etiology, defined by a wide spectrum of organ involvement occurring on a background of fatigue, fever, joint pain and weight changes, and a chronic evolution with exacerbations alternating with quiescent disease [1, 4, 6, 8]. It develops predominantly in women of their reproductive age, making pregnancy a major concern in routine practice; lupus women have higher risk for infertility, miscarriages, and other pregnancy complications due to disease activity, renal involvement, medications (e.g. cyclophosphamide), and presence of certain autoantibodies (anti- Ro/SSA, anti-La/SSB, antiphospholipid antibodies) [4, 10, 12].

The outcomes of lupus pregnancies have dramatically improved over the last decade thanks to advance understanding of disease and its effects in the body, pregnancy planning, multidisciplinary management and close monitoring [1–6]. However, there are clear differences between pregnancy in general population and lupus pregnancy. While a healthy pregnancy is widely defined by specific immunological and hormonal changes, underlying lupus pregnancy is characterized by higher serum pro-inflammatory cytokines, lesser Th2 polarization, lower estrogen and progesterone levels, lower number of T-Reg defective cells, blockade of complement inhibitors by anti-phospholipid antibodies (aPL), increased placental complement component deposition, aberrant activation and, finally, local inflammation. In another words, we talk about an altered physiological response, leading to significant pregnancy morbidity in lupus patients [1–4, 10].

Furthermore, the physiological modulation of the immune system by pregnancy and related hormonal changes may interact with disease activity in autoimmune rheumatic disorders and drive complications (e.g. disease flares); on the other hand, lupus may have a significant impact on pregnancy outcomes [1, 2, 4, 10]. Disease activity, severity of organ damage, antibody profile and drug treatment may promote maternal (e.g. preeclampsia) and fetal complications (pregnancy loss, intra-uterine growth retardation, preterm birth, even neonatal lupus) [1, 4, 9, 10].

Pregnancy in lupus is still considered at increased risk for adverse pregnancy outcomes (APOs) [1–10]. Pregnant SLE-women can develop in 19–57% cases severe obstetric complications including spontaneous abortion (SA), preeclampsia (PE), intrauterine growth restriction (IUGR), small for gestational age (SGA), preterm birth, fetal death in utero and neonatal death. APOs particularly develop if significantly longer disease duration and higher disease activity 6 preconceptual months, during pregnancy and 6 months postpartum period [1, 4, 9, 10, 12, 13]; furthermore, active SLE at the time of conception is a strong predictor of APOs and current recommendations consider disease quiescence for 6 months prior to conception [1, 4, 10, 12, 13].

A detailed look to one of the most important multiethnic cohort of lupus patients in the PROMISSE (*Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus*) prospective study revealed APOs in 19% of pregnancies, with fetal and neonatal death in 4% and 1%, respectively, preterm delivery in 9%, and small-for-gestationalage neonate in 10% suggesting how important is to accurately identify, counsel, and manage lupus patients in order to optimize their pregnancy outcomes [1, 14–17].

#### **3. Biomarkers in lupus pregnancy**

A *biomarker* is an indicator of normal biological processes, pathogenic processes or responses to an intervention [16]. Besides their triple diagnostic, prognostic and therapeutic value, biomarkers have major implications in personalized medicine [1, 2, 4, 16].

Specific biomarkers and novel serum or urine biomarkers may represent the best choice to classify stage and treat patients with SLE; an extended list includes complement level, specific antibodies level, CXCL10, Galectin 9, SIGLEC-1, IL-1 family, BAFF family, lymphocyte populations as serum biomarkers, as well as urine biomarkers [16].

In an attempt to identify biomarkers in lupus pregnancy, pivotal studies suggested that active disease, prior nephritis, use of antihypertensive medications, antiphospholipid antibodies (aPL), hypocomplementemia and anti-double stranded DNA (anti-dsDNA) antibodies are highly associated with APOs [1, 4, 9, 10].

We will further focus on different APOs in lupus, emphasizing the role of biomarkers in stratifying risks and, eventually, driving a more personalized approach in lupus pregnancy.

#### **3.1 Impact of pregnancy on SLE**

#### *3.1.1 Lupus flares associated with pregnancy*

It is well known that 40 to 60% of women with SLE will experience a flare during pregnancy or the first post-partum year; moreover, disease can exacerbate *Challenges in the Delivery Room: Integrated Analysis of Biomarkers Predicting Complications… DOI: http://dx.doi.org/10.5772/intechopen.96099*

at any time during pregnancy and postpartum period, without any clear pattern [1, 2, 4–6, 8]. Commonly utilized instruments to asses disease activity in non-pregnant lupus patients have been specifically adapted and validated for the use in pregnant women [5, 6, 8, 18–20]; *SLE Disease Activity Index in Pregnancy* (SLEPDAI), *modified-SLE Activity Measure for Pregnancy* (m-SLAM) and *Lupus Activity Index in Pregnancy* (LAI-P) and are able to detect changes in disease activity in pregnancy, to monitor and to diagnose flares of maternal disease during gravidity, without mistaking signs and symptoms physiologically associated with pregnancy [1, 4, 5, 8, 18, 21].

According to their severity, lupus flares may be classified as *mild flares* (involving skin and joints), with no major impact on pregnancy outcomes, and *severe flares* (in which kidney features, significant hematologic, serositis and severe arthritis may develop) with poor pregnancy outcomes [1, 2, 5, 6, 8].

Most of lupus exacerbations during pregnancy and postpartum period had mucocutaneous, renal and hematological involvement; additionally, postpartum 6-month period appears to have the highest risk for disease exacerbation and up to 50% of flares in postpartum are severe according to a recent analysis [1, 4–8, 10, 13].

SLE flares critically depend on disease activity 6 to 12 months prior to the conception suggesting that pregnancy outcomes are optimal when disease is in complete clinical remission for 6–12 months before conception; besides, there is a 2 to 4 times risk of flare if active lupus before pregnancy, and a SLEDAI≥4 points 6 months before pregnancy and lupus nephritis are main predictors of adverse maternal outcomes [1, 4–8].

Several factors should be considered for risk stratification in SLE women in preconception [1, 4–10] (**Table 1**).

Biomarkers predicting lupus flare in pregnancy may be classified in three main categories, as follows [1, 4–8, 10]:

Although it is widely recognized that low C3 and C4 levels are associated with active SLE, it seems that low complement occurring during SLE pregnancy may predict APOs [1, 4, 6–8, 22]. Recent data confirm that low C4 at preconception predict flares during pregnancy and suggest that complement evaluation during pregnancy is suitable to detect the high-risk patients that require a more vigilant SLE monitoring and management [23]. Surprisingly, the same study failed to demonstrate any statistical correlation between lupus flare and anti-dsDNA positivity, disease activity (SLEDAI at preconception visit and SLEPDAI during pregnancy), antiphospholipid antibodies positivity as well as clinical SLE manifestations [1, 4–8, 18, 24].

#### **Table 1.**

*Risk stratification of SLE in preconception period.*

#### **Table 2.**

*Differences between lupus flare and physiological pregnancy changes.*

On the other hand, many authors reported that disease activity during pregnancy increases the risk of APO, while patients with sustained low lupus disease activity scores have significantly lower APO rates [8, 13, 18].

Recognizing a lupus flare can be difficult given that normal changes related to pregnancy can mimic lupus activity [1, 4, 10]. Main clinical and lab assessment in lupus flare and normal pregnancy are summarized in table above (**Table 2**).

Serological biomarkers are suitable for monitoring lupus activity, but serological activity that develops during pregnancy, especially in the context of clinical activity, may be associated with increased risk for pregnancy loss, intrauterine growth restriction and preterm birth [1, 4–10].

Finally, the so-called *'critical' clinical and serological lupus phenotypes* define patients at increased risk for pregnancy complications; such phenotypes require a special monitoring during pregnancy and encompass for past or present history of lupus nephritis, anti-Ro/SSA and/or La/SSB positivity and aPL positivity or SLE associated with APS [1, 4–10].

#### *3.1.2 Lupus nephritis and pregnancy*

It is basically recognized that renal activity may be associated with APOs, requiring a strict follow-up based on urine protein excretion, urine sediment analysis (haematuria, urinary casts) as well as serum creatinine level and glomerular

*Challenges in the Delivery Room: Integrated Analysis of Biomarkers Predicting Complications… DOI: http://dx.doi.org/10.5772/intechopen.96099*

filtration rate [1, 2, 4–9]. Moreover, urinary levels of CXCL10, and CXCL16 are highly increased in lupus nephritis, TCD4 cells may be an indicator of all treatment response and CCL2 sensitive indicator of renal flare [16].

Recommendations for the approach of pregnancy in the context of lupus nephritis have been released by *European League Against Rheumatism* (EULAR) in 2017. Severe renal flares during pregnancy not responding to drugs with an acceptable safety profile (azathioprine, antimalarials) warrant for a complex, multidisciplinary management, with potential early termination of pregnancy and/or use of embryotoxic drugs if required. [4, 6–8, 25–28].

Several practical points should be emphasized as follows:

#### **3.2 Impact of SLE on pregnancy**

#### *3.2.1 Pre-eclampsia (PE)*

Considered as a syndrome unique to pregnancy, preeclampsia remains a significant maternal complication in lupus pregnancy [1, 4–10] and a challenge in clinical practice. Key parameters that allow us to distinguish between PE and SLE activity are listed below (**Table 3**) [1, 4–8, 10, 22, 29]. Interestingly, serologic biomarkers can also distinguish between SLE flare (decreased serum C3 and C4 levels associated with increased anti-dsDNA concentrations) and pre-eclampsia. [4, 7, 8, 22, 24].

*Mild PE* refers to the new onset of hypertension (≥140/90 mmHg) associated with proteinuria (≥300 mg/24 h urine specimen) after 20 weeks of gestation in a previously normotensive women, while *severe PE* account for new onset proteinuric hypertension and at least one of the following: thrombocytopenia (less than 100.000 platelets/mm3 ), symptoms of central nervous system dysfunction, proteinuria ≥5 g/24 h and oliguria, liver involvement (serum transaminase at least twice normal), severe blood pressure elevation (≥160/110 mmHg). It is undoubtedly associated with high risk for stroke, preterm birth, death and eclampsia [1, 4, 10].

Furthermore, preeclampsia should also be differentiated by active lupus nephritis and there are several clinical and lab parameters that help to correctly assess the patient and recognize the renal involvement or pregnancy complication (**Table 4**) [1, 4, 10].

Finally, biomarkers predicting preeclampsia in lupus are already documented, as follows [4, 8, 22, 29, 30]:

• *SLE-specific factors -* active lupus nephritis (especially class III or IV), renal failure at the time of conception, sustained use of prednisone (≥ 20 mg/day during pregnancy), thrombocytopenia, active SLE at conception, low C4, anti-RNP positivity, presence of aPL antibodies; and

• *Maternal factors -* age ≥ 40 years, previous personal or family history of preeclampsia, pre-existing hypertension or diabetes, multiple pregnancies, obesity, low pro-angiogenic factors (VEGF, PIGF1), high anti-angiogenic factors (sFlt-1, soluble endoglin), increased vascular resistance in uterine artery with deficient spiral artery remodeling.

The use of vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and FMS–like tyrosine kinase-1(sFlt-1) are useful for the differential diagnosis between nephritis and preeclampsia [1, 4, 10].

Asymptomatic aPL-positive patients (without any pregnancy complications or history of thrombosis) are not generally treated with prophylactic therapy to prevent pregnancy loss. However, presence of aPL regardless of clinical history is considered a risk factor for development of preeclampsia [4, 5, 8, 10, 22, 29].

Although the outcomes of lupus pregnancy have dramatically improved, *pregnancy loss, preterm birth, low birth weight and cesarean section* are still reported in such patient population [1, 4, 9, 10].


**3. Materials and Methods**

#### *3.1. Plant Materials*

We picked the experimental materials from Nujiang Lisu Autonomous Prefecture, Yunnan Province. Inflorescences of *L. yunnanensis* were collected, bottled, and brought back to Kunming for subsequent use. The blooming flowers of five individuals collected within LLO (Table 6) were frozen immediately in liquid nitrogen and stored at −80 ◦C for use as transcriptome sequencing materials. The plant samples were mixed, and RNA was extracted using an RNA extraction kit from TransGen (Beijing, China). Transcriptomic sequencing was performed at Beijing Novogene Biological Information Technology Co., Ltd., Beijing, China. Based on the results of previous investigations into the resource status of *L. yunnanensis*, 6 populations were selected as primer polymorphism detection materials in regions with a dense distribution and adequate quantity, and where sampling was convenient and relatively representative. These were GDX, GCG, FMM, FPK, LLO, and LCM (Table 6).


Preface

Medical imaging was primarily seen as the use of non-invasive techniques to create internal images of the human body for clinical or medical purposes. This rapidly evolving field of medicine originated in the first decade of the 19th century, when Wilhelm Röntgen, a professor of physics at Würzburg University in Germany, discovered electromagnetic radiation. After the World War Two, the development of computer technology has triggered an amazing revolution in medical imaging techniques.

What we know about and do with medical imaging has changed tremendously over the past decade, beginning with the basics, following with the breakthroughs, and moving on to the abstract.

There is a continuous drive not only to improve the diagnostic yield of medical imaging techniques for clinical use, but also the management of the huge amount of digital information available to medical imaging departments. Today there is an increasing interest to harness medical imaging processes to improve research in the biophysical domain.

Medical imaging has experienced tremendous progress during the past decade. Continuous innovations have been fueled by the need to improve diagnostic yield and achieve fast turnaround through robust information management, which should ultimately improve patient outcome. The rapid changes in digital technology have also created opportunities for the development of high-tech equipment employed in medical imaging practice.

Incidentally, these changes tend to revolve around key modalities such as radiography, computed tomography, scintigraphy, magnetic resonance imaging and ultrasound. In many instances, one modality tends to augment the limitations associated with others. This book approaches the concept of medical imaging from a wider perspective not considered by many authors in this area. It consists of four sections and eighteen chapters and topics.

The first section deals with basic concepts such as identification of structures in medical images, 3D image segmentation, image analysis, texture analysis, radiation protection and simulations.

#### X Preface

Section two concentrates on the image processing techniques, quality metrics as well as tools required to optimize patient processes.

Section three deals with applications of medical techniques in clinical settings, while the last section explores the advances made in this area including PET/CT hybrid technique, optical imaging thermography, mitosis detection, phase contrast microscopy and use in image-guided surgery.

It is hoped that this book bridges the gap between the core clinical books reserved for medical diagnosis and the wide ranging possibilities in the field of biological research. It is a must-read for all practitioners and researchers interested in medical imaging.

This book is an attempt to present the old, understand the current and appreciate the great advancements into the future of medical imaging. It will be an invaluable resource to those interested in history, clinical applications and unlimited horizons presented by medical imaging science.

My acknowledgement goes to all the authors, who have made scholarly contributions to the book from diverse backgrounds. I am also grateful and indebted to the publishing process managers Bojana Zelenika and Marija Radja for carefully directing the editorial process and for their patience even when I couldn't meet the scheduled timeline.

> **Felix Okechukwu Erondu Ph.D**  Adjunct Senior Lecturer in Radiography and Medical Imaging University of Nigeria Nigeria

X Preface

timeline.

Section two concentrates on the image processing techniques, quality metrics as well

Section three deals with applications of medical techniques in clinical settings, while the last section explores the advances made in this area including PET/CT hybrid technique, optical imaging thermography, mitosis detection, phase contrast

It is hoped that this book bridges the gap between the core clinical books reserved for medical diagnosis and the wide ranging possibilities in the field of biological research. It is a must-read for all practitioners and researchers interested in medical imaging.

This book is an attempt to present the old, understand the current and appreciate the great advancements into the future of medical imaging. It will be an invaluable resource to those interested in history, clinical applications and unlimited horizons

My acknowledgement goes to all the authors, who have made scholarly contributions to the book from diverse backgrounds. I am also grateful and indebted to the publishing process managers Bojana Zelenika and Marija Radja for carefully directing the editorial process and for their patience even when I couldn't meet the scheduled

**Felix Okechukwu Erondu Ph.D**

University of Nigeria

Nigeria

Adjunct Senior Lecturer in Radiography and Medical Imaging

as tools required to optimize patient processes.

microscopy and use in image-guided surgery.

presented by medical imaging science.

**Part 1**

**Basic Concepts in Medical Imaging**


**1. Introduction**

The link between Corporate Social Responsibility (CSR) and Firm Financial Performance (FFP) remains one of the most controversial issues during the past fifty years. Despite the extensive research, both theoretical and empirical carried out in different contexts; it seems that no consensus has been reached on causality, sign and even less on its shape. On a theoretical level, the arguments in favor of a positive relationship are mainly found in the social impact hypothesis defended by the stakeholder approach according to which good stakeholder management would generate better performance. In contrast, the trade-off hypothesis stemming from a liberal view postulates that CSR would divert the company from its main mission of profit maximization Friedman [1]. Regarding the causality of the relationship, two hypotheses are also theoretically defensible: on the one hand, it is the Available Fund Hypothesis [2, 3] that would play an initiating element in CSR practices. This hypothesis is based on Slack Resource Theory [4, 5], maintaining that availability of financial resources would encourage

companies to get involved in CSR activities, [6, 7]. On the other hand, according to the Managerial Opportunism Hypothesis [8], good financial performance would push managers to reduce their commitment to CSR actions to increase short-term profitability as well as their personal remuneration. Conversely, poor financial performance would lead to an increase in social spending in order to divert attention and justify their poor performance [8, 9]. On an empirical level, the researches carried out to date do not seem to have been sufficient either to draw a definitive conclusion as to the relationship between CSR and financial performance. Indeed, these investigations do not allow us to rule on a general and stable relationship between CSR and performance given many contingent factors that affect this relationship. In recent Meta-analysis, [10, 11] conclude that even if empirical research on the CSR-FFP relationship favors a positive link, the latter would be affected by several contingent variables (moderators and mediators). Thus, several variables are likely to influence this relationship such us firm size [12], firm' origin country [13], Competition intensity within the industry [14], Industry [15, 16], earning management [17], ownership concentration [18], R and D expenditures [19], leadership styles [20], cultural differences and the crucial role that owner-managers could play when dealing with CSR agenda [21].

Furthermore, others arguments have been put forward to justify the lack of consensus on the nature of this relationship, such as the difficulties and biases related to the operationalization of CSR, the performance measurement indicators retained as well as the delay effects necessary to be able to judge the interaction between the two variables [22]. At last, some other recent empirical research questions the linearity of the relationship - when it exists - evoking cubic, or quadratic forms [23, 24]. Thus, specifying the nature of the relationship between CSP and FFP is a very "challenging task". According to legitimacy theory [25], a firm needs to appropriate certain legitimacy granted by the stakeholders. Indeed, Stakeholders tend to pay more attention, surveillance and exert more intense pressure on the most visible companies by their size, their industry, their presence in the media …. The response to these different pressures depends on the firm's Corporate Social Responsiveness as firms may tend to manage their legitimacy according to the intensity of the pressures to which they are subject. Thus, CSR commitment would be a way of responding to various pressures whose intensity depends on the degree of visibility of the company. The main arguments put forward to justify the impact of organizational visibility on social performance relate to the fact that large companies are supposed to be more visible would be subject to greater pressure from stakeholders to encourage them to consolidate their legitimacy. Much more, firm visibility has been identified as a factor impacting the social performance by recent empirical work [26, 27]. On the other hand, by reducing information asymmetry, firm visibility is supposed to attract more investor's attention. Investors could better assess the company's financial performance and make predictions on firm prospects. Firm visibility could also be affected by its sustainable innovation commitment. Cillo et *al.*, [28], conducted a systematic literature review on this subject emphasizing the need for companies to adopt a collaborative approach with different stakeholders to implement new products and processes suggesting that firms should develop organizational and individual capabilities by integrating external sources of information while adopting sustainable innovation strategies. Previous studies have also indicated that organizational visibility could reduce the cost of equity, which can improve a company's financial performance [29]. Additionally, under tighter control from external stakeholders, visibility decrease agency costs and increase financial performance by reducing free cash flow to managers. Given the reduction in the cost of equity and agency cost and easy access to greater financial and political resources, visibility could improve the financial performance of the company.

*The Moderating Effect of Firm Visibility on the Corporate Social Responsibility-Firm Financial… DOI: http://dx.doi.org/10.5772/intechopen.95861*

In other words, visibility is probably going to increase the company's exposure to implied claims. Thus, when these complaints are ignored by management, they might impact the performance of the company and compromise its legitimacy since as the firm visibility increases, the involvement of the general public in a company increases, initiatives will become more and more necessary leading to more social involvement.

However, if firm visibility is liable to affect CSR on one hand and financial performance on the other hand, it will probably be a moderating variable in the CSR-FFP relationship. Hence, our research aims to test the impact of CSR on FFP and to highlight the moderating effect of firm visibility on this relationship on a sample of large French companies. This study makes three contributions to the literature. First, it provides proof of the significant impact of visibility on CSR. Then, it contributes to the literature on CSR by presenting visibility as a predictor of CSR initiatives. Third, this study demonstrates that visibility has a moderating effect on the link between CSR and FFP.

The remainder of this study will be organized as follows: Section 2 represents the research hypothesis, Section 3 describes the methodology, Section 4 provides the results and discussion of results and Section 5 presents the conclusion and recommendations.

## **2. Theoretical framework and hypotheses**

CSR can be defined as the commitment to an improvement process in which companies integrate social, environmental, and economic considerations into management in a voluntary, systematic, and consistent manner with their stakeholders. Two theories are likely to shed light on the behavior of the company in society. Firstly, stakeholder theory [30] suggests that the success of the company depends on its ability to develop and maintain exchanges and transactions involving several resources with the various stakeholders [31]. It also recognizes that the expectations and interests of stakeholders are varied and sometimes contradictory [32]; it would therefore be called upon to take care of a real dialog to reply to its conflicting expectations and continually seek their support. From this angle, CSR is considered as a form of a dialog between the company and the various stakeholders. Secondly, legitimacy theory postulates that organizations continually seek to confirm that they operate within the bounds and in step with the standards of their respective Societies. According to Chiu and Sharfman [33], any institution – firms in particular - operates in society through an explicit or implicit contract. This continuous look for legitimacy could depend upon the degree of exposure of the firm to the assorted stakeholders and so, on the degree of its visibility. Indeed, visibility increases the company's exposure to implicit claims, media, and the general public and can therefore lead to higher CSR; visibility is more consistent and a more powerful predictor of CSR initiatives than other factors previously studied [34].

#### **2.1 Direct relationship between CSR and firm financial performance**

Stakeholder theory [30], has marked the literature on the relationship between CSR and company performance [11, 35]. It states that if a company satisfies its stakeholders, by carrying out social projects, for instance, it will improve its image and reputation, and thereby it's financial performance [4]. However, if the company fails to achieve a positive social impact, this will create fears among its stakeholders about its image which will increase costs and decrease profits [36]. A company that seeks to reduce its implicit costs (environmental costs, product quality costs, etc.)

#### *Corporate Social Responsibility*

through irresponsible social actions should face higher explicit cost (reputation, payment of penalties, etc.). This will have a negative effect on its profitability and competitiveness. Therefore, authors who support this view predicting a positive correlation between CSR and FFP. This assumption is called "positive social impact" or "good management". According to Cristache et al*.* [37], integration of social responsibility dimensions into companies' strategies, would help to increase their long-term performance.

According to the legitimacy theory, CSR legitimizes firm's businesses and guaranteed their existence [38]. Thus, the disclosure of the assorted CSR activities expected and desired by Society, make it possible to legitimize their commercial activities and failure to go with this instruction compromises overall profitability.

Resource Based View approach [39] suggests that by satisfying the expectations of stakeholders, the company develops inimitable and non-substitutable resources and skills. These resources can be intangible assets [40] such as innovation, human capital, leadership, etc. If the company manages to create and exploit these new resources, it will be able to develop sustainable competitive advantages [41].

Signaling theory [42] also provided an argument for the positive impact of CSR on financial performance. Thus, through their social achievements and especially through their disclosure, companies will try to send a positive signal in order to obtain a positive response from the market.

On an empirical level, several researchers have concluded a positive link between CSR and financial performance. Laskar [43] detected a positive relationship between CSR scores (based on content analysis) and Market-to-Book Value (MBV) on a sample of 119 large Southeast Asian companies over the period 2009–2014. By adopting the same approach, Nguyen [44] established a positive link between CSR scores and ROA on a sample of 31 Vietnamese commercial banks. Choi et al. [45] were also able to conclude that there is a positive link between philanthropic commitment (as an indicator for measuring CSR) and ROA; their research focused on 11,000 observations over the period 2002–2014 in Korea.

In Europe, Rodríguez-Fernández [46] constructed a social behavior index to show the existence of a positive relationship between this index and financial performance apprehended by both ROA, ROE and Tobin's Q; their study focused on a sample of 107 companies listed on the Madrid stock exchange. Adeneye and Ahmed [47] also found a positive link between CSR scores and market to book value (MBV) on a sample of 500 British companies. More recently, in a recent second-order Meta analysis, covering 25 primary Meta analyzes, 1274 empirical researches, or nearly one million observations, Busch and Fried [10] concluded that a positive and highly significant relationship between CSR and financial performance.

Based on theoretical justifications, empirical literature and our research questions, we make the following central hypothesis (H1):

**H1:** CSR is positively related to firm financial performance.

#### **2.2 Moderating effect of firm visibility**

Firm visibility describes the extent to which companies are observed by their stakeholders. It can be viewed as a unique attribute that reflects the exposure and attractiveness of a firm [48]. Visibility is a concept close to reputation. However, it is necessary to make a distinction: if the reputation reflects the image stakeholders have of the firm (good or bad), visibility mainly reflects the presence and 'observability' within the community and it is related to the level of 'stakeholder recognition' [49].

#### *The Moderating Effect of Firm Visibility on the Corporate Social Responsibility-Firm Financial… DOI: http://dx.doi.org/10.5772/intechopen.95861*

Such presence can be affected by size, brand, impact on the natural environment, employability, presence in the media but also by various scandals within which firm may well be involved. Firm visibility could be the source of an "excess" of pressure and oversight on the part of stakeholders, since they have more information on corporate social responsibility. Thus, companies with high visibility are more likely to obtain more positive responses from their external stakeholders prompting them to improve their social performance, with more effort in terms of innovation. On the other hand, companies with high visibility can attract more attention from investors. Additionally, visibility may be a recognizable attribute that can help customers differentiate them from other businesses [50]. In keeping with Pfeffer and Salancik [51], external stakeholders are more curious about visible firms which affect the intensity of the pressures they are subjected to. Visible firms would be under more public scrutiny. Hörisch et al. [52, 53] noted that the more exposed position lead to higher public pressure and more CSR activities.

Firm visibility also can reduce information asymmetry degree between companies and their stakeholders and amplify the information disclosed by companies [54]. Thus, companies with higher visibility are more likely to elicit adverse reactions from their stakeholders. For example, within the case of high firm visibility of companies, violations of environmental regulations are going to be particularly pronounced [55], to which investors react strongly negatively. Additionally, a high firm visibility can even allow customers to understand their environmental irresponsibility [56]. Wu et *al.* [57] underlines the existence of a correlation between positive stakeholder's responses and firm's level visibility. Visible companies are likely to attract and gain support of community stakeholders as well as favorable evaluations from regulatory stakeholders. Likewise, CSR practices are expected to increase firm visibility which might help talented workers attraction as an effective knowledge management spillover [58]. The authors showed empirically the positive effect of a firm's CSR practices, operating in knowledge-based industries, on attracting highly skilled workers, thus enhancing the company's competitiveness.

Finally, the active CSR behaviors of companies are much easier to know by governments allowing them to access preferential policies, like access to bank loans, tax deductions and market access that stimulate social innovation [33]. Therefore, we make the subsequent assumption:

**H2:** Firm visibility strengthen the positive effect of CSR on Firm Financial performance

**Figure 1.**

*The research design is presented in Figure 1.*


**4.5 TUSC permutation**

The Tile Usage of Sub-channels is a downlink subcarrier permutation mode that is identical to the uplink PUSC. If closed loop advanced antenna systems (AAS) are to be used with the PUSC mode, explicit feedback of the channel state information (CSI) from the MS to the BS would be required even in the case of TDD, since the UL and DL allocations are not symmetric, and channel reciprocity cannot be used. TUSC allows for a DL allocation that is symmetric to the UL PUSC, thus taking advantage of UL and DL allocation symmetry and eliminating the requirement for explicit CSI feedback in the case of closed-loop AAS for TDD systems. Refer to TTD frame structure shown in Fig. 10.


*3.1. Phase Transition Analysis*

The XRD patterns were evaluated using Highscore software v5.1, while the identification of the peaks was conducted using the PANalytical 2021 database. The peak search was realized considering only those with a minimum significance of 5.00, and a peak base with Gonio of 2.00, through the minimum second derivative method.

The XRD analysis of the CA samples (Figure 3) confirms the presence of multiple phases, such as quartz (96-900-9667), calcite (96-900-0967), anorthite (96-900-0362) and hematite-proto (96-900-2163). The detected hematite-proto contains Fe, H and O. Moreover, the XRD pattern of the metakaolin showed a high content of a typical amorphous structure. Compared to the CA pattern, the one specific to MK showed multiple peaks with high intensity. The most significant peak is positioned close to 25◦ (2θ) and corresponds to kaolinite (96-900-9231), the second peak, positioned close to 12.5◦ (2θ) corresponds to the same phase, while the peak close to 26.6◦ (2θ) corresponds to quartz (96-900-9667). Close to 35◦ (2θ) multiple peaks confirm the presence of muscovite (96-901-4938), while chloritoid (96-900-5444) was detected with the most significant peak close to 20◦ (2θ). The detected kaolinite contains Al, Si and O, the detected quartz contains Si and O, the detected muscovite contains K, Al, Si and O and the detected chloritoid contains Al, Fe, Mg, Si and O. As can be seen from Figure 3, in the case of MK, almost all of the identified peaks confirm the presence of kaolinite, quartz, muscovite and chloritoid.

**Figure 3.** The XRD pattern of the raw materials used in this study.

In the case of MT, the XRD pattern confirmed the presence of multiple phases rich in Fe or Si. Accordingly, quartz (96-901-5023), hematite (96-901-5965), pyrite (96-900-0595), calcium cyclo-hexaaluminate (96-100-0040) and hydrazinium copper sulfide (96-430-7636) were detected.

Due to the reaction between the activator and the aluminosilicate source, the dissolution of aluminates and silicates occurred, resulting in disordered and amorphous silicophosphate (Si–P), aluminophosphate (Al–P) or silico-alumino-phosphate (Si–Al–P) gels. However, the differences between the XRD spectra of the raw materials and the spectra of the acid-activated geopolymers are low because the Si–P, Al–P and Si–Al–P phases are typically amorphous (Figure 4). The existence of quartz and kaolinite at the same position was evident in previous studies [24,25]. Moreover, it can be observed that, due to the geopolymerisation reaction, multiple peaks disappeared, such as the peak around 22◦ (2θ) and the one around 29.5◦ (2θ). In addition, the intensity of the peaks decreased significantly. However, one new peak can be observed around 40.5◦ (2θ).

The calcite disappearance from the CA after the reaction with the phosphoric acid, i.e., the peak around 28◦ (2θ), disappeared due to geopolymerisation. This could be attributed to brushite formation or to the following chemical reaction (Equation (1)):

$$\text{3Ca}^{2+} + \text{2PO}\_4^{3-} + \text{H}\_2\text{O} = \text{3CaO} - \text{P}\_2\text{O}\_5 \text{ - H}\_2\text{O (C-P-H gel)}\tag{1}$$

In a phosphate acid environment, the Al oxides will be dissolute after the Ca compounds; therefore, the C–P–H gel will be formed before Al-P [10]. Therefore, by comparing the samples with MK against those without MK, it can be stated that the samples with higher Ca content will exhibit a lower setting time, due to the solubility differences between the divalent metals and the trivalent one.

**Figure 4.** The XRD pattern of the acid-activated geopolymers without mine tailings.

The broad peak at 27◦ (2θ) indicates the formation of the berlinite phase (AlPO4) which has a similar XRD pattern to quartz and will confer high mechanical properties to the final geopolymer [10,26]. Moreover, by comparing the XRD pattern of the MK with that of MK–geo, it can be observed that all of the peaks between at 26◦ (2θ) and 35◦ (2θ) appeared due to the reaction between the acid and the raw material. Furthermore, the intensity of all the peaks specific to kaolinite have been reduced.

In addition, as observed in [27,28], multiple Al–O–P phases, such as phosphotridymite, phosphocristobalite, aluminium phosphate or aluminium phosphate hydroxide appear, but they overlap with the patterns of other phases. However, a hydrated form of aluminium phosphate confirmed as metavariscite was detected [29].

In the samples with mine tailings (Figure 5), the characteristic diffraction of anhydrite (CaSO4) disappeared, which indicates that the structures of CaSO4 were dissolute due to the phosphoric acid presence. Furthermore, the resulting Ca contributes to the formation of brushite or amorphous calcium phosphate [30] and as crystalline ettringite in Aft and Afm monosulfate [31,32]. In addition, the peak around 12◦ (2θ), which corresponds to hydrazinium copper sulfide, increased significantly in the MTCA geopolymer.

**Figure 5.** The XRD pattern of the acid-activated geopolymers with mine tailings.


**Acknowledgements**

This research was funded by the National Science and Engineering Research Council (NSERC) and the ENMAX Corporation under the Industrial Research Chairs programme. Important additional support came from he Schulich endowment to the University of Calgary and the Egyptian Higher Ministry of Education. We thank Heath Raftery for the data in Figure 3.