الفهرس 
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Abstract
This current study aimed to evaluate the association of angiotensin converting enzyme (ACE), angiotensin converting enzyme-2 (ACE2), angiotensin 2 (Ang-II) and angiotensin 1-7 (Ang 1-7) with the cardiovascular diseases (CVDs) in chronic hemodialysis (HD) patients. We also analyzed their dynamic changes in the course of a single HD session. In addition, their role in the prediction of CVDs and their prognostic significance were studied as well.
The current prospective case-controlled hospital based study was carried out in the HD unit of Nephrology Department of El-Minia University Hospital along the period between June 2018 and November 2020.
The current study included the following groups:
group I: It included 58 HD patients with obvious clinical evidence of CVDs including: coronary artery disease (CAD), valvular heart disease, rheumatic heart disease (RHD), congenital heart disease, peripheral vascular disease (PVD) and cerebrovascular stroke. They were 29 men and 29 women and their ages ranged from 20 to 77 years old with mean± standard deviation (SD) of 49.52 ± 14.97.
group II: It included the 22 HD patients without obvious clinical evidence of the previous aforementioned CVDs. They were 6 men and 16 women and their ages ranged from 18 to 73 years old with mean± SD of 44.55 ± 17.37.
group III: It comprised of 20 healthy apparently volunteers. They were 9 men and 11 women and their ages ranged from 20 to 75 years old with mean± SD of 47.80 ± 15.53.
As regarding HD.groups, we excluded the following criteria:
(1) Patients aged <18years.
(2) Duration of HD sessions <3 months.
(3) Usage of renin inhibitors, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs).
(4) Patients with positive serum marker of anti-hepatitis C virus antibody (anti-HCVAb), hepatitis B surface antigen (HBsAg) and human immunodeficiency virus antibody (HIVAb).
(5) Alcohol or illicit drug abusers.
(6) Malignancies.
(7) Usage of immunosuppressive drugs.
(8) Renal artery stenosis.
All the study subjects were submitted to:
I) Thorough clinical history (for both HD patients and control groups).
II) Careful clinical evaluation (for both HD patients and control groups).
III) Dialytic session data assessment (for HD patients group).
IV) Laboratory Investigations (for both HD patients and control groups) that included:
Complete blood count (CBC)
Glycated hemoglobin (HbA1c)
Parathyroid hormone related protein (PTHrP)
Prothrombin time and concentration
Chemical analyses of fasting serum and two hours (hrs) postprandial glucose levels, liver function tests (LFTs), alkaline phosphatase (ALP), serum creatinine, urea, uric acid, total cholesterol (TC), triglycerides (TGs), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C).
Fasting serum insulin
Assessment of insulin resistance (IR) by calculation of homeostasis model assessment- insulin resistance (HOMA-IR) score according to the standard equation:
Homeostasis model assessment- insulin resistance (HOMA-IR) = fasting insulin concentration [micro international unit (μIU)/milliliters (ml)] × FSG [millimole (mmol)/liter (l)] /22.5
Electrolytes including sodium, potassium, calcium, magnesium and phosphorus.
Serum viral markers including anti-HCVAb, HBsAg and HIVAb.
Iron profile including serum iron and total iron binding capacity (TIBC). In addition, transferrin saturation (TSAT) was assessed according to the standard equation:
Transferrin saturation (TSAT) =(Serum iron [microgram(µg)/deciliter (dl)]/Total iron binding capacity (TIBC) [µg/ dl])X100
Serum ferritin
High sensitive C -reactive protein (Hs CRP).
Serum levels of ACE and ACE2 [before (pre) and after (post) HD session].
Serum levels of Ang II and Ang 1–7 [before (pre) and after (post) HD session].
V) Assessment of hydration state (for HD patients group) using body composition monitor™ (BCM™).
VI) Imaging studies (for HD patients group) that included:
Chest X-ray.
Bilateral carotid duplex.
Electrocardiogram (ECG) assessment.
Transthoracic echocardiogram (TTE) assessment.
The current study revealed that the HD patients and healthy controls were comparable as regards age, gender, residence, PVD history, cerebrovascular stroke history and body mass index (BMI). However, HD patients had statistically significant higher proportion of current smoking, hypertensionو diabetes mellitus, systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared with controls.
HD patients and healthy controls were comparable as regards white blood cells (WBCs) count, platelet count, prothrombin time (PT), prothrombin concentration (PC), fasting serum glucose (FSG) and HbA1c. However, HD patients had statistically significant lower values of hemoglobin, red blood cells (RBCs) count, hematocrit (HCT) value, aspartate transaminase (AST), alanine aminotransferase (ALT), serum albumin, total protein (TP), uric acid, potassium, magnesium, total calcium, corrected calcium, HDL-C, ACE2 and Ang 1-7, whereas they had statistically significant higher values of ALP, creatinine, urea, sodium, phosphorus, calcium x phosphorus product, parathyroid hormone (PTH), TC, TGs, LDL-C, fasting serum insulin, HOMA-IR, Hs CRP, serum iron, TIBC, TSAT, serum ferritin, ACE and Ang-II compared with controls.
Cardiac HD patients had statistically significant higher proportion of urban residence, hypertension, diabetes mellitus and longer duration of dialysis and higher values of SBP, DBP, erythropoietin stimulating agents (ESAs) dosage and longer duration of ESAs treatment, whereas they had statistically significant lower values of Kt/V (K -dialyzer clearance of urea; t -dialysis time; V -volume of distribution of urea) compared with non-cardiac HD patients.
Cardiac HD patients had statistically significant lower values of hemoglobin, RBCs count, HCT, serum albumin, TP, magnesium, HDL-C, ACE2 and Ang 1-7, whereas they had statistically significant higher values of WBCs count, ALT, total calcium, corrected calcium, phosphorus, calcium x phosphorus product, TC, TGs, LDL-C, Hs CRP, serum ferritin, ACE and Ang-II compared with non-cardiac HD patients.
Cardiac HD patients had statistically significant higher values of absolute over-hydration (AOH), relative fluid overload (RFO), total body water (TBW) volume, extracellular water (ECW) volume, ratio of extracellular to intracellular water (E/I), lean tissue index (LTI), lean tissue mass (LTM) and body cell mass (BCM) compared with non-cardiac HD patients.
Cardiac HD patients had statistically significant higher proportion of electrocardiograhic axis deviation, arrhythmias and left ventricular hypertrophy (LVH) compared with non-cardiac HD patients.
Cardiac HD patients had statistically significant higher values of both right and left carotid intimal medial thickness (CIMT) and higher proportion of calcified atheromatous plaque and multiplicity of plaques, whereas they had statistically significant lower values of right internal carotid artery (ICA), end-diastolic velocity (EDV) and left ICA EDV compared with non-cardiac HD patients.
Cardiac HD patients had echocardiographic LVH (74.1%), pulmonary arterial systolic pressure (PASP) ≥35% (46.6%), atherosclerotic ascending aorta (44.8%), valvular calcification (41.4%), left ventricular ejection fraction (LVEF) <50% (22.4%)و significant valvular regurge (10.3%), and pericardial effusion (1.7%).
Cardiac HD patients had statistically significant higher values of echocardiograhic interventricular septum thickness at end-diastole (IVSd), interventricular septum thickness at end-systole (IVSs), left ventricular internal dimension at end-diastole (LVIDd), left ventricular internal dimension at end-systole (LVIDs), left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular posterior wall thickness at end-systole (LVPWs), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), aortic root (AO) diameter and left atrium diameter (LAD) and higher proportion of LVH, atherosclerotic ascending aorta and valvular calcification, whereas they had statistically significant lower values of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) compared with non-cardiac HD patients.
AOH had statistically significant positive correlation with IVSd, LVIDs, ESV and AO diameter and statistically significant negative correlation with LVEF and LVFS. Also, it showed that RFO had statistically significant positive correlation with IVSd, IVSs, LVIDd, LVIDs, LVPWd, LVPWs, ESV, Ao diameter and pulmonary arterial systolic pressure (PASP) and statistically significant negative correlation with LVEF and LVFS. Furthermore, it showed that TBW volume had statistically significant positive correlation with IVSd, IVSs, LVPWd, Ao diameter and LAD. Moreover, it showed that ICW volume had statistically significant positive correlation with IVSd, IVSs, LVPWd and Ao diameter. It also showed that ECW volume had statistically significant positive correlation with IVSd, IVSs, LVPWd, Ao diameter and LAD. In addition, it showed that E/I had statistically significant positive correlation with IVSd and Ao diameter
Older age and higher values of SBP, DBP, WBCs count, phosphorus, ACE and Ang-II and lower values of total calcium, ACE2 and Ang 1-7 were associated with arrhythmias. These factors remained independently statistically significant predictors when we used simple logistic regression analysis.
Higher proportion of diabetes mellitus and higher values of SBP, platelet count, ALP, uric acid, TC, LDL-C, Hs CRP, serum ferritin, ACE and Ang-II and lower values of HDL-C, ACE2 and Ang 1-7 were associated with increased CIMT. These factors remained independently statistically significant predictors when we used simple logistic regression analysis apart from diabetes mellitus and uric acid.
Older age and higher values of SBP, DBP, TC, TGs, LDL-C, FSG, HOMA-IR, Hs CRP, serum ferritin, ACE and Ang-II and lower values of HDL-C, ACE2 and Ang 1-7 in were associated with calcified atheromatous plaque. These factors remained independently statistically significant predictors when we used simple logistic regression analysis.
Male gender, higher proportion of current smoking and higher values of SBP, WBCs count, ALP, uric acid, corrected calcium, phosphorus, calcium x phosphorus product, PTH, TC, TGs, LDL-C, Hs CRP, ACE and Ang-II and lower values of serum albumin, HDL-C, ACE2 and Ang 1-7 were associated with atherosclerotic ascending aorta. These factors remained independently statistically significant predictors when we used simple logistic regression analysis apart from uric acid and corrected calcium.
Higher proportion of hypertension and higher values of ALP and HbA1c and lower values of ACE2 were associated with echocardiograhic LVH. Only HbA1c and ACE2 remained independently statistically significant predictors when we used simple logistic regression analysis.
Higher proportion of current smoking and lower values of magnesium were associated with increased PASP which remained independently statistically significant after adjustment for possible confounding variables using simple logistic regression analysis.
Higher values of SBP, phosphorus, calcium x phosphorus product, TC, TGs, LDL-C, Hs CRP, serum ferritin, ACE and Ang-II and lower values of serum albumin, HDL-C, ACE2 and Ang 1-7 were associated with valvular calcification. These factors remained independently statistically significant predictors when we used simple logistic regression analysis apart from phosphorus.
Higher BMI was associated with decreased LVEF in cardiac HD patients which remained independently statistically significant after adjustment for possible confounding variables using simple logistic regression analysis. None of the studied markers had impact on LVEF.
Higher values of ACE and Ang-II and lower values of ACE2 and Ang 1-7 were associated with increased SBP and DBP.
In the course of single HD session, cardiac HD patients had statistically significant lower values of pre-dialytic levels of ACE and Ang-II compared to their post-dialytic levels and higher values of pre-dialytic levels of ACE2 and Ang 1-7 compared to their post-dialytic levels.
Our study revealed that ACE, ACE2, Ang-II and Ang 1-7 were statistically significant predictors for CVDs events in HD patients.
When these results were incorporated into receiver operating characteristics (ROC) curve analysis, we found that the ACE with a cut-off value of greater than 19 was statistically significant predictor of CVDs events with a sensitivity of 100%, a specificity of 81.82%, positive predictive value (PPV) of 93.5%, negative predictive value (NPP) of 100% and diagnostic accuracy of 95%. The ACE2 with a cut-off value of less than or equal to 74 was statistically significant predictor of CVDs events with a sensitivity of 98.28%, a specificity of 100%, PPV of 100%, NPP of 95.7% and diagnostic accuracy of 98.75%.The Ang-II with a cut-off value of greater than 69 was statistically significant predictor of CVDs events with a sensitivity of 84.48%, a specificity of 100%, PPV of 100%, NPP of 71% and diagnostic accuracy of 88.8%. The Ang 1-7 with a cut-off value of less than or equal to 47 was statistically significant predictor of CVDs events with a sensitivity of 89.66%, a specificity of 100%, PPV of 100%, NPP of 78.6% and diagnostic accuracy of 92.5%.
Our study showed a mortality a proportion of 31% in cardiac HD patients vs. 13.6% in non-cardiac HD patients.
Older age, diabetes mellitus, HbA1c, HOMA-IR, serum ferritin, arrhythmias, CIMT >9 mm, AOH, RFO, ACE, ACE2, Ang-II and Ang 1-7 were associated with all-cause mortality in HD patients.
Conclusions:
Increased levels of ACE and Ang-II and decreased plasma levels of ACE2 and Ang 1–7 were detected in the HD patients (either cardiac or non-cardiac) compared with healthy volunteers.
Increased levels of ACE and Ang-II and decreased plasma levels of ACE2 and Ang 1–7 were observed in the cardiac HD patients compared with non-cardiac HD patients.
Cardiac HD patients are more overhydrated than non-cardiac HD patients.
The excess fluid may lead to adverse effects on dynamic echocardiographic parameters and thereby, adverse cardiac outcomes.
Increased levels of ACE and Ang-II and decreased levels of ACE2 and Ang 1–7 were significantly associated with CVDs progression.
Increased levels of ACE and Ang-II and decreased levels of ACE2 and Ang 1–7 had more sensitive and specific values for CVDs events prediction in HD patients.
Single HD session could increase levels of ACE and Ang-II and decrease levels of ACE2 and Ang 1–7 in the cardiac HD patients.
Increased levels of ACE and Ang-II and decreased levels of ACE2 and Ang 1–7 were associated with all-cause mortality in HD patients.
Limitations
The relatively small sample size and cardiovascular events.
The monocentric nature of the study.
Recommendations:
Further larger and long term prospective multicenter studies are needed to assess the role of ACE, Ang-II, ACE2 and Ang 1–7 more accurately in cardiovascular complications in HD patients.
Each of ACE, Ang-II, ACE2 and Ang 1–7 should be considered as important implicating factors for CVDs outcomes and mortality among HD patients.
Pharmacological strategies that currently used to modulate the adverse cardiovascular effects of increased ACE and Ang-II and decreased ACE2 and Ang 1–7, specifically ACEIs and ARBs should be administrated after the HD session as they can offer beneficial outcomes in cardiovascular morbidity and mortality in HD patients.